Triazole compounds and the use thereof as dopamine-D3 -ligands

ABSTRACT

Triazole compounds of the following formula:                    
     where Ar 1 , A, B and Ar 2  have the meanings given in the description, possess a high affinity for the dopamine D 3  receptor and can therefore be used for treating diseases which respond to dopamine D 3  ligands.

This application is a 371 of PCT/EP98/04138 filed Jul. 3, 1998.

The present invention relates to triazole compounds and to the use of such compounds. The compounds mentioned have valuable therapeutic properties and can be used for treating diseases which respond to dopamine D₃ receptor ligands.

Compounds of this type having physiological activity have been disclosed. U.S. Pat. Nos. 4,338,453; 4,408,049 and 4,577,020 describe triazole compounds which have antiallergic or antipsychotic activity. DE-A 44 25 144 and WO 97/25324 describe triazole compounds which respond to dopamine D₃ receptor ligands. Compounds of the same structural type, however with other heterocycles in place of the triazole ring are disclosed in DE-A-44 25 146, DE-A-44 25 143 and DE 44 25 145.

Neurons obtain their information by way of G protein-coupled receptors, inter alia. A large number of substances exert their effect by way of these receptors. One of these substances is dopamine.

It is known with certainty that dopamine is present and that it has a physiological function as a neurotransmitter. Cells responding to dopamine are connected with the etiology of schizophrenia and Parkinson's disease. These and other diseases are treated with drugs which interact with the dopamine receptors.

Prior to 1990, two dopamine receptor subtypes were clearly defined pharmacologically, ie. the D₁ and D₂ receptors.

More recently, a third subtype has been found, ie. the D₃ receptor, which appears to mediate some of the effects of the antipsychotic drugs. (J. C. Schwartz et al., The Dopamine D₃ Receptor as a Target for Antipsychotics, in Novel Antipsychotic Drugs, H. Y. Meltzer, Ed. Raven Press, New York 1992, pages 135-144)

D₃ receptors are principally expressed in the limbic system. It is therefore assumed that a selective D₃ antagonist would probably have the antipsychotic properties of the D₂ antagonists but would not have their neurological side effects. (P. Solokoff et al., Localization and Function of the D₃ Dopamine Receptor, Arzneim. Forsch./Drug Res. 42(1), 224 (1992); P. Solokoff et al. Molecular Cloning and Characterization of a Novel Dopamine Receptor (D₃) as a Target for Neuroleptics, Nature, 347, 146 (1990)).

Surprisingly, it has now been found that certain triazole compounds exhibit a high affinity for the dopamine D₃ receptor and a low affinity for the D₂ receptor. These compounds are therefore selective D₃ ligands.

The present invention relates, therefore, to compounds of the formula I:

where

Ar¹ is phenyl, naphthyl or a 5- or 6-membered heterocyclic aromatic ring having from 1, 2, 3 or heteroatoms which are independently selected from O, S and N, where Ar¹ may have 1, 2, 3 or 4 substituents which are selected, independently of each other, from C₁-C₆-alkyl, which may be substituted by OH, OC₁-C₆-alkyl, halogen or phenyl, C₁-C₆-alkoxy, C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₃-C₆-cycloalkyl, halogen, CN, COOR², NR²R², NO₂, SO₂R², SO₂NR²R², or phenyl, which may be substituted by C₁-C₆-alkyl, OC₁-C₆-alkyl, NR²R², CN, CF₃, CHF₂, or halogen, and where the heterocyclic, aromatic ring mentioned may be fused to a phenyl ring;

A is straight-chain or branched C₄-C₁₀-alkylene or straight-chain or branched C₃-C₁₀-alkylene which comprises at least one group Z which is selected from O, S, NR², CONR², COO, CO, or a double or triple bond,

B is a radical of the formula:

or, if Ar¹ represents the 5- or 6-membered, heterocyclic or aromatic ring which may be substituted as indicated, B may also be a radical of the formulae

Ar² is phenyl, pyridyl, pyrimidinyl or triazinyl, where Ar² may have from 1 to 4 substituents which are selected, independently of each other, from OR², C₁-C₆ alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, C_(l)-C₆-alkoxy-C_(l)-C₆-alkyl, halogen-C₁-C₆-alkyl, halogen-C₁-C₆-alkoxy, halogen, CN, NO₂, SO₂R², NR²R², SO₂NR²R², a 5- or 6-membered carbocyclic, aromatic or non-aromatic ring and a 5- or 6-membered, heterocyclic aromatic or non-aromatic ring having 1 or 2 heteroatoms which are selected from O, S and N, where the carbocyclic or heterocyclic ring may be substituted by C_(l)-C₆-alkyl, phenyl, phenoxy, halogen, OC₁-C₆-alkyl, OH, NO₂ or CF₃ and where Ar² may be fused to a carbocyclic or heterocyclic ring of the above-defined nature,

R¹ is H, C₃-C₆-cycloalkyl or C₁-C₆-alkyl which may be substituted by OH, OC₁-C₆-alkyl or phenyl;

the radicals R², which can be identical or different, are H or C₁-C₆-alkyl, which may be substituted by OH, OC₁-C₆-alkyl or phenyl;

and their salts with physiologically tolerated acids.

The novel compounds are selective dopamine D₃ receptor ligands which act in a regioselective manner in a limbic system and which, due to their low affinity for the D₂ receptor, have fewer side effects than the classic neuroleptics, which are D₂ receptor antagonists. The compounds can therefore be used for treating diseases which respond to dopamine D₃ receptor antagonists or dopamine D₃ receptor agonists, eg. for treating diseases of the central nervous system, in particular schizophrenia, depressions, neuroses, psychoses, parkinson and anxiety.

Within the context of the present invention, the following expressions have the meanings given in conjunction with them: Alkyl (also in radicals such as alkoxy, alkylamino, etc.) is a straight-chain or branched alkyl group having from 1 to 6 carbon atoms and, in particular, from 1 to 4 carbon atoms. The alkyl group can have one or more substituents which are selected, independently of each other, from OH, OC₁-C₆-alkyl, halogen or phenyl.

Examples of an alkyl group are methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, t-butyl, etc.

Cycloalkyl is, in particular, C₃-C₆-cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

Alkylene radicals are straight-chain or branched. If A does not have any group Z, A then comprises from 4 to 10 carbon atoms, preferably from 4 to 8 carbon atoms. The chain between the triazole nucleus and group B then has at least 4 carbon atoms. If A has at least one of said Z groups, A then comprises from 3 to 10 carbon atoms, preferably from 3 to 8 carbon atoms.

If the alkylene groups comprise at least one of the Z groups, these may either be arranged in the alkylene chain at an arbitrary site or in position 1 or 2 of group A (seen from the Ar¹ radical). The radicals CONR² and Coo are preferably arranged such that the carbonyl group is facing the triazole ring. Particularly preferred are compounds of the formula I in which A is —Z—C₃-C₆-alkylene, in particular —Z—CH₂CH₂CH₂—, —Z—CH₂CH₂CH₂CH₂—, —Z—CH₂CH=CHCH₂—, —Z—CH₂C(CH₃)=CHCH₂—, —Z—CH₂C(=CH₂)CH₂—, —Z—CH₂CH(CH₃)CH₂— or a linear —Z—C₇-C₁₀-alkylene radical, with Z being attached to the triazole ring. Z is preferably CH₂, O and in particular S. Further preferably is A —(CH₂)₄—, —(CH₂)₅—, —CH₂CH₂CH=CHCH₂—, —CH₂CH₂C(CH₃)═CHCH₂—, —CH₂C(═CH₂)CH₂—, or —CH₂CH₂CH(CH₃)CH₂—.

Halogen is F, Cl, Br or I.

Haloalkyl can comprise one or more, in particular 1, 2, 3 or 4, halogen atoms which can be located on one or more C atoms, preferably in the α- or ω-position. CF₃, CHF₂, CF₂Cl or CH₂F are particularly preferred.

Acyl is preferably HCO or C₁-C₆-alkyl-CO, in particular acetyl. When Ar¹ is substituted, the substituent can also be located on the nitrogen heteroatom.

Preferably, Ar¹ is

where

R³ to R⁶ are H or the abovementioned substituents of the radical Ar¹,

R⁷ is H, C₁-C₆-alkyl or phenyl, and

X is N or CH. If the phenyl radical is substituted, the substituents are preferably in the m position or the p position.

Particularly preferably, Ar¹ is

where R³ and R⁴ have the abovementioned meanings. The phenyl, pyrazinyl and pyrrole radicals which are indicated are particularly preferred.

The radicals R³ to R⁶ are preferably H, C₁-C₆-alkyl, OR², CN, phenyl which may be substituted by C₁-C₆-alkyl, C₁-C₆-alkoxy or halogen, CF₃ and halogen and, in particular, H, C₁-C₆-alkyl, OR² and halogen. In this context, R² has the abovementioned meanings.

The radical B is preferably

The radical Ar² may have one, two, three or four substituents, preferably one or two substituents, which are located, in particular, in the m position and/or the p position. They are preferably selected, independently of each other, from C₁-C₆-alkyl, haloalkyl, NO₂, halogen, in particular chlorine, phenyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, cyclopentyl and cyclohexyl. When one of the substituents is C₁-C₆-alkyl, a branched group and, in particular, isopropyl or t-butyl is preferred.

Ar² is preferably unsubstituted or substituted phenyl, 2-, 3- or 4-pyridinyl or 2-, 4(6)- or 5-pyrimidinyl.

When one of the substituents of the radical Ar² is a 5- or 6-membered heterocyclic ring, the ring is then, for example, a pyrrolidine, piperidine, morpholine, pyridine, pyrimidine, triazine, pyrrole, thiophene, or pyrazole radical, with a pyrrole, pyrrolidine, pyrazole or thienyl radical being preferred.

When one of the substituents of the Ar² radical is a carbocyclic radical, this latter radical is then, in particular, a phenyl, cyclopentyl or cyclohexyl radical.

When Ar² is fused to a carbocyclic radical, this latter radical is, in particular, a naphthalene or dihydro- or tetrahydro-naphthalene radical.

According to an embodiment the invention relates to compounds of formula I, wherein Ar¹ is a heterocyclic aromatic ring as defined above, B is

and A and Ar2 have the meanings given above.

The invention also encompasses the acid addition salts of the compounds of the formula I with physiologically tolerated acids. Examples of suitable physiologically tolerated organic and inorganic acids are hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, oxalic acid, maleic acid, fumaric acid, lactic acid, tartaric acid, adipic acid or benzoic acid. Other useful acids are described in Fortschritte der Arzneimittelforschung [Advances in drug research], Volume 10, pages 224 ff., Birkhäuser Verlag, Basle and Stuttgart, 1966.

The compounds of formula I can have one or more centers of asymmetry. The invention therefore also includes the relevant enantiomers and diastereomers in addition to the racemates. The respective tautomeric forms are also included in the invention.

The process for preparing the compound (I) comprises

a) reacting a compound of the formula (II)

where Y¹ is a customary leaving group such as Hal, alkanesulfonyloxy, arylsulfonyloxy, etc., with a compound of the formula (III)

or

b) reacting a compound of the formula (IV)

where Z¹ is O, NR², or S and A¹ is C₁-C₁₀-alkylene or a bond, with a compound of the formula (V)

where Y¹ has the abovementioned meaning and A² is C₂-C₁₀-alkylene, where A¹ and A² together have from 3 to 10 C atoms and A¹ and/or A² optionally comprises at least one group Z; or

c) reacting a compound of the formula (VI)

where Y¹ and A¹ have the abovementioned meanings, with a compound of the formula (VII)

where Z¹ has the abovementioned meanings; or

d) reversing the polarity of a compound of the formula (VIII)

using reagents which are known from the literature, such as 1,3-propanedithiol, KCN/water, TMSCN or KCN/morpholine, as described, for example, in

Albright Tetrahedron, 1983, 39, 3207 or

D. Seebach Synthesis 1969, 17 and 1979, 19 or

H. Stetter Angew. Chem. Int. Ed. 1976, 15, 639 or

van Niel et al. Tetrahedron 1989, 45, 7643

Martin et al. Synthesis 1979, 633,

to give the products (VIIIa) (using 1,3-propanedithiol by way of example)

and then chain-elongating with compounds of the formula (IX)

where Y¹ has the abovementioned meanings and A³ is C₃-C₉-alkylene, which may comprise a group Z

to give after deprotecting and reducing, compounds of the formula (Ia)

where Z² is CO, or a methylene group, and Z² and A² together have from 4 to 10 C atoms; or

e) reacting a compound of the formula (VIII) with a compound of the formula X

where Y² is a phosphorane or a phosphonic acid ester, by a method analogous to customary methods, as described, for example, in Houben weyl “Handbuch der Organischen Chemie” [Handbook of organic chemistry], 4th edition, Thieme Verlag Stuttgart, Volume 5/1b p. 383 ff. or Volume 5/1c p. 575 ff.

The process for preparing a compound of the formula I where A comprises the group COO or CONR² comprises in reacting a compound of the formula (XI)

where Y³ is OH, OC₁-C₄, Cl or, together with CO, is an activated carboxyl group, and A⁴ is C₀-C₉-alkylene, with a compound of the formula (XII)

where Z³ is OH or NH₂.

The compounds of the formula (III) are starting compounds for preparing compounds of the formulae (V), (VII) and (XII), and are prepared by standard methods as described, for example, in J. A. Kiristy et al., J. Med. Chem. 1978, 21, 1303 or C. B. Pollard, J. Am. Chem. Soc. 1934, 56, 2199 or by

a) reacting, in a known manner, a compound of the formula (XIII)

where Q is H or a customary amine protecting group, with a compound of the formula (XIV)

where Y⁴ is B(OH)₂, —SnR₃ (R³=butyl or phenyl), trifluoromethanesulfonyloxy, or has the meanings given for Y¹, and R is C₁-C₄-alkyl; or

b) reacting a compound of the formula (XV)

where B¹ is

where Q is H or a customary amino protecting group, eg. butyloxycarbonyl, benzyl or methyl, and Y⁴ is a leaving group, eg. OTf, SnBu₃, B(OH)₂ or halogen, with a compound of the formula (XIVa)

where Y⁵ is a boron derivative, such as B(OH)₂, or a metal-containing leaving group, for example SnR₃ (R₃=butyl or phenyl) or zinc halide, if Y⁴ is halogen or trifluoromethylsulfonyloxy, or Y⁵ is halogen or trifluoromethylsulfonyloxy, if Y⁴ is a boron derivative, such as B(OH)₂, or a metal-containing leaving group, for example SnR₃ or zinc halide, as described in

S. Buchwald et al. Angew. Chem. 1995, 107, 1456 or J. F. Hartwig et al. J. Am. Chem. Soc 1996, 118, 7217 or

S. Buchwald J. Org. Chem. 1997, 62, 1264 or F. Kerrigan et al., Tetrah. Lett. 1998, 39, 2219 and the literature cited in that document, or

J. K. Stille, Angew. Chem. 1986, 98, 504 or

J. K. Stille et al. J. Org. Chem. 1990, 55, 3014 or

M. Pereyre et al. “Tin in Organic Synthesis”, Butterworth 1987; or

c) reacting a compound of the formula (XVI)

where Q has the abovementioned meanings, with a compound M—Ar², where M is a metal such as Li, or MgY⁶, and y⁶ is Br, Cl or I. M—Ar² can be obtained from compounds of the formula (XIV) using methods which are known from the literature, or

d) preparing a compound of the formula (XVII)

wherein B² is

and Q has the abovementioned meaning, by reduction, for example hydrogenations of compounds of the general formula Q-B³-Ar² (IIIa), wherein B³ is one of the abovementioned unsaturated radicals B, using methods which are known from the literature.

Compounds of type B are either known or are obtained in a similar way to know methods as e.g. 1,4-diazacycloalkanes: L. Borjeson et al., Acta Chem. Scand. 1991, 45, 621; Majahrzahl et al. Acta. Pol. Pharm., 1975, 32, 145; 1-azacycloheptanones: A. Yokoo et al., Bull Chem. Soc. Jpn. 1956, 29, 631 and WO 97/25324.

In the above formulae, Ar¹, R¹, A, B, Z and Ar² are as defined above.

Compounds of the Ar¹-triazole, Ar₂, Ar¹ type are either known or can be prepared using known methods, as described, for example, in S. Kubota et al. Chem. Pharm. Bull 1975, 23, 955 or A. R. Katritzky, C. W. Rees(ed.) “Comprehensive Heterocyclic Chemistry”, Pergamon Press, or “The Chemistry of Heterocyclic Compounds”’ J. Wiley&Sons Inc. NY and the literature cited in that document.

The compounds of the formula VIII are novel and are likewise part of the subject-matter of the present invention.

Compounds of the (VIII) and (XI) type, where A is C₀-alkylene, can be prepared by metallating the 3-aryl-5-H-1,2,4(4H)-triazoles

and by a method similar to methods described in T. Kauffman et al. Angew. Chem. Int. Ed. Engl. 1972, 11, 846 or by A. R. Katritzky, C. W. Rees(ed.) “Comprehensive Heterocyclic Chemistry”, Pergamon Press Vol. 5, p 753.

The novel compounds and the starting materials and intermediates can also be prepared by a method similar to the methods described

The above-described reactions generally take place in a solvent at between room temperature and the boiling temperature of the solvent employed. Examples of solvents which can be used are esters, such as ethyl acetate, ethers, such as diethyl ether or tetrahydrofuran, dimethylformamide, dimethyl sulfoxide, dimethoxyethane, toluene, xylene, ketones, such as acetone or methyl ethyl ketone, or alcohols, such as ethanol or butanol.

If desired, the reaction can be carried out in the presence of an acid binder. Suitable acid binders are inorganic bases, such as sodium or potassium carbonate, sodium or potassium hydrogen carbonate, sodium ethoxide or sodium hydride, or organometallic compounds, such butyllithium, or alkylmagnesium compounds, or organic bases, such as triethylamine or pyridine. The latter can simultaneously serve as solvents.

The reactions may be carried out using a catalyst, such as transition metals and their complexes, eg. Pd(PPh₃)₄, Pd(OAc)₂ or Pd(P(oTol)₃)₄, or using a phase transfer catalyst, eg. tetrabutylammonium chloride or tetrapropylammonium bromide.

The crude product is isolated in a customary manner, for example by filtering, by distilling off the solvent or by extracting from the reaction mixture, etc. The resulting compounds can be purified in a customary manner, for example by recrystallization from a solvent, by chromatography or by conversion into an acid addition compound.

The acid addition salts are prepared, in a customary manner, by mixing the free base with the appropriate acid, where appropriate in solution in an organic solvent, for example a lower alcohol, such as methanol, ethanol or propanol, an ether, such as methyl t-butyl ether, a ketone, such as acetone or methyl ethyl ketone, or an ester, such as ethyl acetate.

When used for treating the abovementioned diseases, the novel compounds are administered orally or parenterally (subcutaneously, intravenously, intramuscularly, or intraperitoneally) in a customary manner. They can also be administered through the nose/throat region using vapors or sprays.

The dose depends on the age, condition and weight of the patient and on the mode of administration. As a rule, the daily dose of active compound is from about 10 to 1000 mg per patient and day in the case of oral administration and from about 1 to 500 mg per patient and day in the case of parenteral administration.

The invention also relates to pharmaceuticals which comprise the novel compounds. These pharmaceuticals are present, in the customary pharmacological administration forms, in solid or liquid form, for example as tablets, film tablets, capsules, powders, granules, coated tablets, suppositories, solutions or sprays. In this context, the active compounds can be worked up together with the customary pharmacological auxiliary substances, such as tablet binders, fillers, preservatives, tablet disintegrants, flowance agents, emollients, wetting agents, dispersants, emulsifiers, solubilizers, retarding agents, antioxidants and/or propellant gases (cf. H. Sucker et al., Pharmazeutische Technologie [Pharmaceutical Technology], Thieme-Verlag, Stuttgart, 1978). The resulting administration forms normally comprise the active compound in a quantity of from 1 to 99% by weight.

The following examples serve to explain the invention without limiting it.

EXAMPLE 1 3-{3-[4-(2-t-Butyl-6-trifluoromethylpyrimidin-4-yl-)piperazin-1-yl]propylmercapto}-4-methyl-5-phenyl-1,2,4-(4H)-triazole

A. Preparation of the Starting Compounds

A.1 2-t-Butyl-4-[4-(3-chloropropyl)piperazin-1-yl]-6-trifluoromethylpyrimidine and 2,2-dimethylpropanimidamide were reacted, in a known manner, with ethyl trifluoroacetate to give 2-(2,2-dimethylethyl)-4-hydroxy-6-trifluoromethylpyrimidine. Heterocyclic Compounds (John Wiley & Sons, 1994, Vol. 52, D. J. Brown (Ed.)).

C₉H₁₁F₃N₂O m.p. 187-188° C.

A.2 After chlorinating with thionyl chloride, the crude product was treated with an excess of anhydrous piperazine, with 2-t-butyl-4-piperazin-1-yl-6-trifluoromethylpyrimidine being obtained.

C₁₃H₁₉F₃N₄ m.p. 78-80° C.

A.3 Alkylating the resulting compound with 1-bromo-3-chloropropane in tetrahydrofuran resulted in 2-t-butyl-4-[4-(2-chloropropyl)piperazin-1-yl]-6-trifluoromethylpyrimidine.

C₁₆H₂₄ClF₃N₄ m p. 83-84° C.

The inserted triazoles were obtained, if not stated otherwise, according to the method of S. Kubota et al., Chem Pharm Bull. 1975,23,955 by reacting the corresponding acid chlorides with alkyl thio semicarbazides in pyridine followed by cyclization in an aqueous solution of sodium hydrogencarbonate or by addition of the corresponding acid hydrazides with aklkyl thio isocyanates in a suitable solvent.

A.4 4-methyl-3-mercapto-5-(thiophen-3-yl-)1.2,4-(4H)-triazole

The sodium salt was isolated.

1H-NMR (DMSO-d₆): 3.7 (3H); 7.5 (m, 2H); 7.8 (m, 1H).

mp: 146° C.

C₇H₆N₃S₂Na (219)

A.5 4-methyl-3-mercapto-5-(2,5-dimethyl-furan-3-yl)-1,2,4-(4H)-triazole

1H-NMR (DMSO-d₆): δ=2.3 (s, 3H); 2.5 (s,3H); 3.7 (s, 3H); 6.1 (s, 1H).

28710/30

A.6 4-methyl-3-mercapto-5-(2,6-dichlor-phenyl)-1,2,4-(4H)-triazole

The sodium salt was isolated.

1H-NMR (DMSO-d₆): δ=3.7 (s, 3H); 7.4 (dd,1H); 7.6 (d, 1H); 8.2 (d, 1H).

mp: 220-225° C.

A.7 4-methyl-3-mercapto-5-(4-methylsulfony-phenyl) 1,2,4-(4H)-triazole

1H-NMR (DMSO-d₆): δ=3.7 (s, 3H); 7.4 (dd, 1H); 7.6 (d, 1H); 8.2 (d, 1H).

mp: 238-239° C.

A.8 4-methyl-3-mercapto-5-(3-bromopyridyl-5)-1,2,4-(4H)-triazole

The sodium salt was isolated.

1H-NMR (DMSO-d₆): δ=3.7 (s, 3H); 8.2(m,1H); 8.9 (m,2H).

A.9 4-methyl-3-mercapto-5-(pyrrol-2-yl)-1,2,4-(4H)-triazole

1H-NMR (DMSO-d₆): δ=3.7 (s, 3H); 6.2(m,1H); 6.8 (1,2H); 7.0 (m, 1H); 11.8 (s, 1H); 14.0 (s, 1H).

mp: 200-201° C.

A.10 4-methyl-3-mercapto-5-(3-benzthienyl)-1,2,4-(4H)-triazole

The sodium salt was isolated.

1H-NMR (DMSO-d₆): 3.8 (s, 3H); 7.5(m,2H); 8.0 (m,3H).

A.11 4-methyl-3-mercapto-5-(4-methyl-thiazol-5-yl)-1,2,4-(4H)-triazole

1H-NMR (DMSO-d₆): 2.4 (s,3H); 3.4 (s, 3H),9.2 (s,1H); 14.1 (s, 1H).

A.12 4-methyl-3-mercapto-5-(6-chlor-biphenyl-2)-1,2,4-(4H)-triazole

1H-NMR (DMSO-d₆): 3.8 (s, 3H), 7.6 (m, 1H), 7.9 (m, 1H); 8.1 (m, 3H); 8.4 (s, 1H).

A.13 4-methyl-3-mercapto-5-(2,4-dinitrophenyl-)-1,2,4-(4H)-triazole

mp: 250-251° C.

MS: m/z=281[M⁺]

A.14 4-methyl-3-mercapto-5-(4-CF₃-phenyl) 1,2,4-(4H)-triazole

MS: m/z=259[M⁺]

A.15 4-propyl-3-mercapto-5-(2-methyloxazol-4-yl)-1,2,4-(4H)-triazole

The potassium salt was isolated.

To a solution of 4.9 g (22.5 mmol) 2-methyloxazol-4-acidhydrazide-bishydrochloride (obtained by hydrazinolysis of the corresponding methyl ester in methanol solution) in 60 ml ethanol were successively added 6.22 g (95 mmol) potassium carbonate and 2.4 ml (23 mmol) propyl isothio cyanate and were 4 h heated to boiling.

The resulting suspension was filtered and concentrated and the residue (6.5 g) was purified by column chromatography (silica gel, methylene chloride-methanol 96:4). Yield: 2.3 g (39% of th.)

1H-NMR (CDCl₃): δ=1.0 (t, 3H); 1.7 (m,2H); 2.6 (s,3H); 4.2 (sm,2H); 8.1 (s,1H); 12.6 (s,1H).

A.16 4-propyl-3-mercapto-5-(2-amino-thiazol-4-yl) 1,2,4-(4H)-triazole

The potassium salt was isolated.

1H-NMR (DMSO-d₆): 0.8 (t,3H); 1.6 (m,2H); 3.4 (s, 2H); 4.3 (m,2H); 7.4 (s,1H); 13.8.

A.17 4-methyl-3-mercapto-5-(5-methylimidazol-4-yl) 1,2,4-(4H)-triazole

The potassium salt was isolated.

1H-NMR (DMSO-d₆): 2.3 (s,3H); 3.4 (s,3H); 7.5 (s,1H).

A.18 4-methyl-3-mercapto-5-(carboxamido) 1,2,4-(4H)-triazole

1H-NMR (DMSO-d₆): 3.7 (s,3H); 7.95 (s,1H); 8.25 (s,1H); 14.2 (s,1H).

MS: m/z=158[M⁺]

A.19 4-methyl-3-mercapto-5-(N-methylpyrrol-2-yl)-1,2,4-(4H)-triazole

10.6 g (101.1 mmol) 4-methyl-3-thio semicarbazide and catalytic amounts of dimethyl amino pyridine were added to 10.2 g (45.1 mmol) 2-trichloracetoxy-N-methylpyrrol (obtained according to Rappoport et al., J. Org. Chem. 1972, 37, 3618) in DMF and heated to 90° C. for 18 h. 77 ml of water were added to the resulting product at room temperature, it as acidified with 10% HCl, stirred for 1 h at 0° C., filtered from the insoluble, and the original solution was extracted with ethyl acetate. The organic layers were dried, evaporated, and the resulting crude product was heated with a 427 ml solution of 1M sodium hydrogen carbonate to boiling. The original solution was filtered off the insoluble after completion of the reaction, was quenched and acidified with concentrated HCl, and the precipitated solid was isolated. Yield: 2.3 g (27% of th.)

MS: m/z=194 [M⁺]

1H-NMR (DMSO-d₆): δ=3.6 (s,3H); 3.9 (s,3H); 6.2 (m,1H); 6.6 (m,1H); 7.1 (m,1H); 14.0 (1H).

B. Preparation of the End Product

576 mg (3 mmol) of 4-mercapto-3-methyl-5-phenyl-1,2,4-(4H)-triazole (prepared in accordance with the method of S. Kubota and M. Uda, Chem. Pharm. Bull. (1975), 23, 955-966 by reacting benzoyl chloride with N-methylthiosemicarbazide and subsequently cyclizing) and 1.1 g (3 mmol) of the chloropropyl compound described above under A.3 were heated, at 100° C. for 6 h, together with 7.2 mg (3 mmol) of lithium hydroxide in 10 ml of dry DMF while stirring. After the mixture had cooled down, 50 ml of water were added and the whole was extracted 3 times with t-butyl methyl ether. The organic phase was dried with sodium sulfate and concentrated by evaporation; the residue was purified by column chromatography (silica gel). The resulting pure substance (920 mg=59%) was subsequently converted into its hydrochloride using ethereal hydrochloric acid.

C₂₅H₃₃ClF₃N₇S (556) m.p. 191-193° C.

The substances of the formula (I) which are listed in the following table were obtained in analogous manner.

TABLE 1 Ex. Ar¹ R¹ A B Ar² Data 1 Phenyl Me —S(CH₂)₃— Piperazinyl

Hydrochloride m.p.: 191-193° C. 2 2,4-Dimethoxyphenyl- Me —S(CH₂)₃— Piperazinyl

Hydrochloride m.p.: 154-157° C. 3 Phenyl Me —S(CH₂)₃— Piperazinyl

m.p.: 91-93° C.; 1H-NMR(DMSO-d₆; ppm), 1.9(q, 2H); 2.45(m, 6H); 3.25(t, 2H); 3.6(s, 3H); 3.75(m, 4H); 7.25(s, 1H); 7.5(m, 3H); 7.8(m, 2H); 8.6(s, 1H). 4 4-CN-Phenyl Me —S(CH₂)₃— Piperazinyl

Hydrochloride m.p.: 82° C. 5 Phenyl Me —S—CH₂—C(═CH₂)—CH₂— Piperazinyl

1H-NMR(CDCl₃; ppm): 2.55 (t, 4H); 3.18(s, 2H); 3.2(t, 4H); 4.0(s, 2H); 5.1(s, 1H); 5.2(s, 1H); 5.85(t, 1H); 6.7(m, 2H); 6.8(d, 1H); 7.2(d, 1H); 7.5(m, 3H); 7.7(m, 2H); 6 Phenyl Me —S(CH₂)₃— Piperazinyl

1H-NMR(CDCl₃; ppm) 2.1(m, 2H); 2.5(m, 6H); 3.3 (t, 2H); 3.8(m, 7H); 4.5(d, 2H); 5.0(t, 1H); 5.2(s, 1H); 6.2(m, 2H); 7.3-7.4(m, 5H); 7.5(m, 3H); 7.6-7.7(m, 4H). 7 Phenyl Me —S(CH₂)₃— Piperazinyl

1H-NMR(CDCl₃; ppm) 2.1(m, 2H); 2.5(m, 6H); 3.4(t, 2H); 3.6(s, 3H); 3.7(m, 4H); 4.1(s, 3H); 5.7(s, 1H); 6.6(d, 1H); 7.3(m, 2H); 7.5(m, 3H); 7.7(m, 3H); 8.2(d, 1H); 8.7(d, 1H). 8 2-iodophenyl phenyl Me —S—CH₂—C(═CH₂)—CH₂— piperazinyl

1H-NMR(CDCl₃; ppm) 1.3(s, 9H); 2.6(m, 4H); 3.1 (s, 2H); 3.3(s, 3H); 3.7(m, 6H); 4.9(s, 1H); 5.1(s, 1H); 6.6(s, 1H); 7.2(t, 1H); 7.4(m, 1H); 7.6(t, 1H); 8.0(d, 1H). 9 4-Me-Phenyl Me —S(CH₂)₃— Piperazinyl

1H-NMR(CDCl₃; ppm) 1.3(s, 9H); 2.0(q, 2H); 2.5 (m, 6H); 3.3(t, 2H); 3.6(s, 3H); 3.7(m, 4H); 6.6(s, 1H); 7.3(d, 2H); 7.6(d, 2H); 10 3-I-Phenyl Me —S(CH₂)₃— Piperazinyl

1H-NMR(CDCl₃; ppm) 1.3(s, 9H); 2.0(q, 2H); 2.4(s, 3H); 2.6(m, 6H); 3.4(t, 2H); 3.6(s, 3H); 3.8(m, 4H); 6.6(s 1H); 7.2(t, 1H); 7.6(d, 1H); 7.85(d, 1H); 8.0ss, 1H);. 11 2-Methoxy- phenyl Me —S(CH₂)₃— Piperazinyl

Fumarate m.p.: 77-80° C. 12 2-Methoxy- Me —S(CH₂)₃— Piperazinyl

Fumarate m.p.: 87-90° C. 13 Phenyl Me —S(CH₂)₃— Piperazinyl

1H-NMR(CDCl₃; ppm) 1.4(s, 9H); 2.1(m, 2H); 2.6 (mbr, 6H); 3.4(t, 2H); 3.6(s, 3H); 3.7(mbr, 4H); 6.7(s, 1H); 7.1(d, 2H); 7.5(m, 3H); 7.6(m, 2H); 8.0(m, 2H); 14 4-tert.- Butyl- phenyl 3- Methoxy- prop-1-yl —S(CH₂)₃— piperazinyl

Hydrochloride m.p.: 102° C. 15 4-tert.-Butyl-phenyl Me —S(CH₂)₃— Piperazinyl

Hydrochloride m.p.: 155° C. 16 2-I-Phenyl Me —S(CH₂)₃— Piperazinyl

1H-NMR(CDCl₃; ppm) 1.3(s, 9H); 1.4(s, 9H); 2.1(q, 2H); 2.6(m, 6H); 3.4(m, 5H); 3.7(m, 4H); 6.3(s, 1H); 7.2(t, 1H); 7.4(d, 1H); 7.5(t, 1H); 7.9(d, 1H). 17 4-Methylphenyl Me —S(CH₂)₃— Piperazinyl

Hydrochloride m.p.: 156-160° C. 18 4-Biphenyl Me —S(CH₂)₃— Piperazinyl

mp.164-165° C. 19 3-I-Phenyl Me —S(CH₂)₃— Piperazinyl

Hydrochloride m.p.: 164-167° C. 20 Phenyl Me —O—(CH₂)₃— Piperazinyl

1H-NMR(CDCl₃; ppm) 1.3(s, 9H); 2.1(m, 2H); 2.6-2.8(m, 6H); 3.5(s, 3H); 3.8(mbr, 4H); 4.6(t, 2H); 6.5 (s, 1H); 7.6(m, 3H); 7.8(m, 2H); 21 Phenyl Me —CH═CH—CH₂—CH₂— Piperazinyl

m.p.: 156-161° C. 1H-NMR(CDCl₃; ppm) 1.3(s, 9H); 1.4(s, 9H); 2.6 (m, 8H); 3.7(m, 7H); 6.2(s, 1H), 6.4(d, 1H); 7.0(td, 1H); 7.5(m, 3H); 7.7(m, 2H). 22 Phenyl Me —(CH₂)₄— Piperazinyl

m.p.: 144-145° C. 23 Phenyl Me —(CH₂)₄— Piperazinyl

1H-NMR(CDCl₃; ppm) 1.3(s, 9H); 1.7(m, 2H); 1.9(q, 2H); 2.4(t, 2H); 2.5(t, 4H); 2.8(t, 2H); 3.6(s, 3H); 3.75(m, 4H); 6.6(s, 1H); 7.4(m, 3H); 7.6(m, 2H);. 24

Me —S(CH₂)₃— Piperazinyl

Hydrochloride m.p.: 190-192° C. 25 Pyrazinylphenyl Me —S(CH₂)₃— Piperazinyl

Hydrochloride m.p.: 164° C. 26 Phenyl Me —S(CH₂)₃— Piperazinyl

1H-NMR(CDCl₃; ppm) 1.5(d, 3H); 2.0(m, 2H); 2.4-2.6(m, 6H); 3.3(t, 2H); 3.6(m, 7H); 5.0-5.2(m, 2H); 5.8(s, 1H); 6.3(m, 2H); 7.2-7.4(m, 8H); 7.5(m, 3H); 7.6(m, 2H); 27 Phenyl Me —S(CH₂)₃— Piperazinyl

1H-NMR(CDCl₃) 1.3(s, 9H); 2.1(m, 2H); 2.5 (m, 6H); 3.4(t, 2H); 3.6(s, 3H). 3.9(t, 4H); 6.3(m, 2H); 6.5 (s, 1H); 7.5(m, 5H); 7.6(m, 2H). 28 3-Thienyl Me —S(CH₂)₃— Piperazinyl

1H-NMR(CDCl₃; ppm) 1.3(s, 9H); 2.0(q, 2H); 2.5 (m, 6H); 3.3(t, 2H); 3.7(s, 3H); 3.75(m, 4H); 6.5(s, 1H); 7.5(m, 2H); 7.8(m, 1H);. 29 3-Thienyl Me —S—CH₂—C(═CH₂)—CH₂— Piperazinyl

1H-NMR(CDCl₃; ppm) 1.3(s, 9H);1.4(s, 9H); 2.6(m, 4H); 3.1(s, 2H); 3.3(s, 3H); 3.7(m, 6H); 4.9(s, 1H); 5.1(s, 1H); 6.3(s, 1H); 7.5(m, 2H); 7.75(m, 1H); 30

Me —S—CH₂—C(═CH₂)—CH₂— Piperazinyl

1H-NMR(CDCl₃) 1.2(s, 6H); 2.2(s, 3H); 2.4(s, 3H); 2.6(m, 4H); 2.9(m, 1H); 3.2(m, 2H); 3.5(br, 5H); 3.7(m, 4H); 3.9(s, 3H); 5.0(s, 1H); 5.15(s, 1H); 6.0(s, 1H); 6.5(s, 1H). 31 Phenyl Me —S(CH₂)₃— Piperazinyl

Fumarate m.p.: 146° C. 34 4-Methyl-phenyl cProp —S(CH₂)₃— Piperazinyl

1H-NMR(CDCl₃): 1.0(m, 4H); 2.0 (q, 2H); 2.4(s, 3H); 2.5(m, 6H); 2.8 (m, 1H); 3.7(mbr, 6H); 6.6(s, 1H); 6.7(s, 1H) 7.3(d, 2H); 7.6(d, 2H). 32 Phenyl Me —S(CH₂)₃— Piperazinyl

1H-NMR(DMSO-d₆) Fumarat: 2.0 (m, 2H); 2.3(s, 3H); 2.7(m, 4H); 2.8 (m, 2H); 3.2(t, 2H); 3.6(s, 3H); 3.7 (m, 4H); 6.6(s, 1H); 6.7(m, 1H); 7.15(d, 1H); 7.5(m, 3H); 7.7(m, 2H); 7.9(m, 1H). 33 Phenyl Me —S—CH₂—C(═CH₂)—CH₂— Piperazinyl

1H-NMR(CDCl₃): 2.5(m, 4H); 3.1 (s, 2H); 3.3(m, 4H); 3.7(s, 2H); 5.1 (s, 1H); 5.2(s, 1H); 6.3(m, 2H); 6.7-6.9(m, 3H); 7.1(m, 2H); 7.4-7.7 (m, 6H). 35 Phenyl iProp —S(CH₂)₃—

1H-NMR(DMSO-d₆) 1.5-2.0(m, 13H); 2.5(m, 4H), 2.7 (m, 2H); 3.4(m, 2H); 3.9(m, 1H); 7.5-7.7(m, 9H.) 36 Phenyl Me —S(CH₂)₃—

1H-NMR(CDCl₃) 2.0(q, 2H); 2.5-2.7(m, 6H); 3.2(m, 2H); 3.5(t, 25H); 6-1(m, 1H); 7.3 (m, 3H); 7.4-7.7(m, 6H). 37 Phenyl nProp —CONH—(CH₂)₄— Piperazinyl

1H-NMR(CDCl₃) 1.0(t, 3H); 1.3(s, 9H); 1.4(s, 9H); 1.6-1.8(m, 6H); 2.6(m, 2H); 2.7 (m, 6H); 3.6(t, 2H); 3.8(m, 4H); 6.3 (s, 1H); 7.5(m, 3H); 7.7(m, 2H). 38 Phenyl Me —S(CH₂)₃— Piperazinyl

1H-NMR(CDCl₃) 2.05(q, 2H); 2.6(t, 2H); 2.7 (m, 4H); 3.2(m, 4H); 3.4(t, 2H); 3.6(s, 3H); 7.4-7.7 (m, 7H); 7.9(d, 1H); 8.1(d, 1H); 8.2(8s, 1H); 9.0(s, 1H). 39 N-methyl-2-pyrrolyl Et —S(CH₂)₃— Piperazinyl

1H-NMR(DMSO-D₆) 1.8-2.0(m, 5H); 2.4(s, 3H); 2.5-2.7(m, 6H); 3.3(m, 2H); 3.7-3.8(m, 7H); 4.0(m, 2H); 6.2(s, 1H); 6.4(m, 1H); 6.6 (m, 3H); 6.9(m, 2H); 7.2 (s, 1H); 7.9(s, 1H); 40 3,4-Dichloro- phenyl Me —S(CH₂)₃—

MS: m/z=473[M⁺] 41

Me —S(CH₂)₃ Piperazinyl

m.p. 154° C. 42

Propyl —S(CH₂)₃— Piperazinyl-

1H-NMR(CDCl₃) 0.9(t, 3H); 1.3(s, 9H); 1.7 (m, 2H); 1.9(m, 2H); 2.3(s, 3H); 2.5(m, 6H); 3.3(m, 2H); 3.7 (m, 1H); 3.8(m, 4H); 4.3 (t, 2H); 6.7(s, 1H); 7.6(s, 1H). 43 Phenyl Me —S(CH₂)₈— Piperazinyl-

Hydrochloride m.p. 146° C. 44 Phenyl Me —S(CH₂)₆— Piperazinyl-

Hydrochloride m.p. 253° C. 45 3-Bromopyri- din-5-yl Me —S(CH₂)₃— Piperazinyl

1H-NMR(CDCl₃) 1.3(s, 9H); 2.1(m, 2H); 2.6 (m, 6H); 3.3(m, 3H); 3.7 (s, 1H); 3.8(m, 4H); 6.6(s, 1H); 8.2(s, 1H); 8.9(m, 2H). 46 3-Thienyl Me —S(CH₂)₃— Piperazinyl

1H-NMR(CDCl₃) 1.0(t, 3H); 1.3(s, 9H); 1.7 (m, 2H), 1.9(m, 2H); 2.6 (m, 8H); 3.4(t, 2H); 3.7 (m, 7H); 6.2(s, 1H); 7.5 (m, 2H); 7.7(s, 1H). 47 4-tert.-Butyl- phenyl- Me —S—CH₂—C(CH₃)═CH₂— Piperazinyl

1H-NMR(CDCl₃) 1.4(2s, 18H); 1.9(s, 3H); 2.5 (t, 4H); 3.0(d, 2H); 3.7(m, 7H); 3.9(s, 2H); 5.5(t, 1H); 6.5 (s, 1H); 7.5(d, 2H); 7.6(d, 2H): 48 Phenyl Propyl —S(CH₂)₃— Piperazinyl

1H-NMR(CDCl₃) 1.3(s, 9H); 1.4(s, 9H); 2.0 (m, 2H); 2.6(m, 6H); 3.3 (t, 3H); 3.6(m, 7H); 6.4(s, 1H); 6.7(s, 1H); 7.4(m, 3H); 7.7 (m, 2H); 49

Propyl —S(CH₂)₃— Piperazinyl

1H-NMR(CDCl₃) 0.9(t, 3H); 1.3(s, 9H); 1.7 (m, 2H); 2.0(q, 2H); 2.5 (m, 6H); 3.3(t, 3H); 3.7 (mbr, 2H); 4.3(t, 2H); 6.2 (s, 1H); 8.9(s, 1H); 50 2-Benzthienyl Me —S(CH₂)₃— Piperazinyl

m.p. 143° C. 51

Me —S—CH₂—C(═CH₂)—CH₂— Piperazinyl

1H-NMR(CDCl₃) 1.2(d, 6H); 1.4(s, 9H); 2.5 (m, 7H); 2.9-3.0(m, 3H); 3.5 (s, 3H); 3.8(s, 2H); 5.0(s, 1H); 5.2(s, 1H); 6.2(s, 1H); 8.9 (s, 1H). 52

Me —S—CH₂—C(═CH₂)—CH₂— Piperazinyl

m.p. 150° C. 53 Phenyl n-Propyl —CO—(CH₂)₃— Piperazinyl

Bishydrochloride 1H-NMR(DMSO-d₆) 1.0(t, 3H); 1.5(s, 9H); 1.7 (m, 2H) 2.2(m, 2H); 3.0 (t, 2H); 3.3(m, 4H); 3.4 (m, 2H); 3.7(m, 3H); 3.9 (m, 4H); 4.5(m, 1H); 5.0 (m, 1H); 7.2(s, 1H); 7.6 (m, 3H); 7.8(m, 2H). 54

Me —S(CH₂)₃— Piperazinyl

Hydrochloride m.p. 150° C. MS: m/z=641[M⁺] 55

Propyl —S(CH₂)₃— Piperazinyl

1H-NMR(CDCl₃) 0.9(t, 3H); 1.3(s, 9H); 1.7 (m, 3H); 1.9(q, 2H); 2.6 (m, 9H); 3.3(t, 2H); 3.7 (m, 4H); 4.3(t, 2H); 6.6(s, 1H); 8.2(s, 1H). 56 2-Pyrrolyl Me —S(CH₂)₃— Piperazinyl

1H-NMR(CDCl₃): 1.0(t, 3H); 1.3(s, 9H); 1.7 (m, 2H); 2.0(m, 3H); 2.5 (m, 8H); 3.3(t, 2H); 3.6(t, 4H); 3.8(s, 3H); 6.2(s, 1H); 6.3 (m, 1H); 6.6(m, 1H); 7.1 (m, 1H). 57

Me —S—CH₂—C(═CH₂)—CH₂—

Hydrochloride m.p. 116° C. 58

Propyl —S—CH₂—C(═CH₂)—CH₂—

Hydrochloride m.p.: 76° C. MS: m/z=525[M⁺] 59 4-Ethinylphenyl Me —S(CH₂)₃— Piperazinyl

MS: m/z=532[M⁺] 60 3-Thienyl Me —(CH₂)₄—

1H-NMR(CDCl₃): 1.7-1.9(m, 4H); 2.5-2.7 (m, 6H); 2.9(t, 2H); 3.2 (m, 2H); 3.7(s, 3H); 7.3-7.5 (m, 6H); 7.8(m, 1H). MS: m/z=395[M⁺] 61 3-Thienyl Me —(CH₂)₄—

1H-NMR(CDCl₃): 1.7-2.0(m, 8H); 2.5(m, 2H); 2.9(t, 2H); 3.1-3.3(m, 4H); 3.7 (s, 3H); 7.5(m, 2H); 7.8 (m, 1H). MS: m/z=393[M⁺] 62 3,4-Dichloro- phenyl Me —(CH₂)₄— Piperazinyl

1H-NMR(CDCl₃): 1.3(s, 9H); 1.4(s, 9H); 1.7 (m, 2H); 1.9(m, 2H); 2.5 (m, 6H); 2.9(t, 2H); 3.6-3.8 (m, 7H); 6.2(s, 1H); 7.4(dd, 1H); 7.6(d, 1H); 8.2(d, 1H). 63 N-Methyl-2- pyrrolyl Et —(CH₂)₄— Piperazinyl

1H-NMR(CDCl₃): 1.3(s, 9H); 1.7-2.0(m, 6H); 2.5(m, 6H); 2.9(t, 2H); 3.7-4.1 (9H); 6.2(s, 1H); 6.4(m, 1H); 6.6(s, 1H); 6.8(m, 1H). 64 3-Bromopyri- din-5-yl cProp —S(CH₂)₃— Piperazinyl

1H-NMR(CDCl₃) 1.0(m, 4H); 1.3(s, 9H); 2.1 (m, 2H); 2.8(m, 1H); 3.6 (m, 6H); 3.3(m, 3H); 3.8 (m, 4H); 6.6(s, 1H); 8.2(s, 1H); 8.9(m, 2H). 65

Me —S(CH₂)₃— Piperazinyl

m.p. 133° C. 66 4-CF₃-Phenyl Me —S(CH₂)₃— Piperazinyl

MS: m/z=576[M⁺] 67 Pyrazinyl Me —S(CH₂)₃—

Hydrochloride m.p. 131° C. MS: m/z=524[M⁺] 68 2,4-Dinitro- phenyl Me —S(CH₂)₃ Piperazinyl

1H-NMR(CDCl₃) 1.3(s, 9H); 1.4(s, 9H); 2.0 (m, 2H); 2.6(m, 6H); 3.3 (t, 3H); 3.8(mbr, 7H); 6.2 (s, 1H); 7.8(d1H); 8.6(dd, 1H); 9.1(d, 1H). 69

Me —S(CH₂)₃—

1H-NMR(CDCl₃) 1.3(s, 9H); 1.9(m, 4H); 2.3(s, 3H); 2.6(m, 4H) 2.8(m, 2H); 3.3(t, 2H); 3.5(mbr, 2H); 3.8 (s, 3H); 3.9-4.1(m, 2H); 6.6 (s, 1H); 7.6(s, 1H); 12.8 (br, 1H). 70

Me —S(CH₂)₃—

1H-NMR(CDCl₃) 1.3(s, 9H); 2.0(m, 4H); 2.3(s, 3H); 2.6(m, 4H); 2.8(m, 2H); 3.3(t, 2H); 3.6(m, 2H); 3.7 (s, 3H); 4.1(m, 2H); 6.6(s, 1H); 8.2(m, 1H); 8.8(m, 2H). 71

Me —S(CH₂)₃—

1H-NMR(CDCl₃) 1.3(s, 9H); 1.8-2.1(m, 4H), 2.6-2.9(m, 6H); 3.1(m, 2H); 3.6(mbr, 2H); 3.8-4.1(m, 5H); 6.6(s, 1H). c = cyclo, for example cProp = cyclopropyl

The compounds of Examples 20-25 and 65 were obtained in the following manner.

EXAMPLE 20 3-{3-[4-(2-t-Butyl-6-trifluoromethylpyrimidin-4-yl)piperazin-1-yl]propoxy}-4-methyl-5-phenyl-1,2,4-(4H)-triazole

855 mg (3mmol) of 3-iodo-4-methyl-5-phenyl-1,2,4-(4H)-triazole (prepared by iodinating 4-methyl-5-phenyl-1,2,4-(4H)-triazole by a method similar to Izv. Akad. Nauk SSSR, Ser. Khim (1975), 616-619), were stirred, at 60° C. for 6 h, with 1.04 g (3 mmol) of 2-t-butyl-4-[4-(3-hydroxypropyl)piperazin-1-yl]-6-trifluoromethyl pyrimidine (prepared, by a method similar to Example 1, A.3, by reacting the product obtained as described in Example 1, A.2 with 3-chloropropanol) and sodium hydride in DMF. For the working-up, ice water was added to the mixture and the whole was extracted several times with methyl t-butyl ether. The residue which was obtained after drying with sodium sulfate and removing the solvent was purified by column chromatography (silica gel, methylene chloride/methanol). Yield, 140 mg (9% of theory) of oil.

C₂₅H₃₂F₃N₇O (503)

1H NMR (CDCl₃): 1.3 (s,9H); 2.1 (m,2H); 2.6-2.8 (m,6H); 3.5 (s,3H); 3.8 (mbr,4H); 4.6 (t,2H); 6.5 (s,1H); 7.6 (m,3H); 7.8 (m,2H);

EXAMPLE 21 3-{4-[4-(2,6-Di-t-butylpyrimidin-4-yl)piperazin-1-yl]but-1-enyl}-4-methyl-5-phenyl-1,2,4-(4H)-triazole

a. 3-Formyl-4-methyl-S-phenyl-1,2,4-(4H)-triazole

18.5 g (116 mmol) of 4-methyl-5-phenyl-1,2,4-(4H)-triazole were dissolved in 235 ml of absolute THF and the solution was cooled down to −70° C.; 85 ml (139 mmol) of a 15% strength solution of butyllithium in hexane were then added at this temperature over the course of 15 min. After 45 min, 72 ml (1.16 mmol) of methyl formate were added over the space of 5 min, in association with which the temperature rose to −50° C. The mixture was subsequently stirred for a further 2 h at −50 to −70° C. and for 30 min at −25° C.; solid ammonium chloride was then added, after which ice water was added and the whole was extracted 3 times with methylene chloride. After drying and evaporating off the solvent, 22.8 g of residue remained, which residue was purified by means of flash chromatography (silica gel, ethyl acetate/methanol).

Yield: 10.9 g (46% of theory)

C₁₀H₉N₃O (187)

1H NMR (CDCl₃): 3.9 (s,3H); 7.6 (m,3H); 7.7 (m,2H); 10.2 (s,1H).

b. 3-[4-(2,6-Di-t-butylpyrimidin-4-yl)piperazin-1-yl]propyl-triphenylphosphonium chloride

3.52 g (10 mmol) of 1-chloro-3-[4-(2,6-di-t-butylpyrimidin-4-yl)piperazin-1-yl]propane (prepared by a method similar to Example 1, A.3) were dissolved, together with 1.8 g of sodium iodide (12 mmol) and 3.41 g (13 mmol) of triphenylphosphine in 75 ml of acetone and the solution was refluxed for 24 h.

After the mixture had been cooled down, the precipitate was filtered off with suction, the filtrate was concentrated by evaporation under reduced pressure and the residue was purified by column chromatography (silica gel, methylene chloride containing 3.5% methanol). Yield: 6.25 g (88% of theory).

C₃₇H₄₈IN₄P (706).

1H NMR (CDCl₃): 1.3 (s,9H); 1.4 (s,9H); 1.9 (m,2H); 2.4 (m,4H); 2.7 (m,2H); 3.6 (m,4H); 3.9 (mbr, 2H); 6.3 (s,1H); 7.6-7.9 (m,15H).

c. 5.88 g (8.3 mmol) of the phosphonium salt which was prepared above under b. were dissolved in 15 ml of ethylene glycol dimethyl ether and the solution was cooled down to 0° C.; 280 mg (9.2 mmol) of sodium hydride were added and, after the mixture had been stirred at room temperature for 15 min, 1.56 g of the aldehyde described above under a., dissolved in 10 ml of ethylene glycol dimethyl ether, were subsequently added dropwise at 0° C.

After the mixture had been stirred at room temperature for 1.5 h and at 40° C. for a further 2 h, it was worked up using toluene and water and the insoluble material was removed by filtration. 2.6 g of oil were obtained from the toluene phase after drying and evaporating. Yield: crude product, 65% of theory.

The product was purified by chromatography (silica gel, methylene chloride/methanol).

C₂₉H₄₁N₇ (487).

1H NMR (CDCl₃): 1.3 (s,9H); 1.4 (s,9H); 2.6 (m,8H); 3.7 (m,7H); 6.2 (s,1H); 6.4 (d,1H); 7.0 (td,1H); 7.5 (m,3H); 7.7 (m,2H).

EXAMPLE 22 3-{4-[4-(2,6-Di-t-butylpyrimidin-4-yl)piperazin-1-yl]butyl}-4-methyl-5-phenyl-1,2,4-(4H)-triazole

a. 2-[4-Methyl-5-phenyl-1,2,4-(4H)-triazol-3-yl]-1,3-dithiane

6.12 g (32.6 mmol) of the aldehyde prepared as described in Example 21 a. were dissolved in 16 ml of chloroform, after which 16 ml of acetic acid, 3.28 ml (32.6 mmol) of 1,3-dimercaptopropane and 160 μl of boron trifluoride etherate were added at 0° C. After the mixture had been refluxed for 2.5 h, a further 2.4 ml of dimercaptopropane and boron trifluoride etherate were slowly added and the mixture was heated for a further 6 h until the aldehyde had been completely reacted.

After the mixture had been cooled down to 0° C., it was adjusted to pH 9-10 with 10% strength sodium hydroxide solution, stirred at 0° C. for 1 h and then extracted 3 times with methylene chloride. 13.2 g of a yellow oil were obtained from the dried and evaporated solvent phase and were purified by column chromatography (silica gel, ethyl acetate). Yield: 4.3 g (48% of theory), colorless solid.

C₁₃H₁₅N₃S₂ (277).

1H NMR (CDCl₃): 2.1 (m,2H); 2.9 (m,2H); 3.3 (m,2H); 3.7 (s,3H); 5.3 (s,1H); 7.5 (m,3H); 7.7 (m,2H).

b. 831 mg (3 mmol) of the above-described dithiane were dissolved in 7.5 ml of dried THF, and the solution was treated, at −70° C., with 2.2 ml (3.6 mmol) of a 15% strength solution of butyllithium in n-hexane. After the mixture had been stirred at from −70° C. to −50° C. for 60 min, 1.06 g (3 mmol) of 1-chloro-3-[4-(2,6-di-t-butylpyrimidin-4-yl)piperazin-1-yl]propane (prepared by a method similar to Example 1, A.3), dissolved in 5 ml of THF, were added dropwise. The mixture was then warmed slowly to room temperature and heated at 30-50° C. for a further 60 min in order to achieve complete reaction. For the working-up, solid ammonium chloride was added to the cooled-down mixture and the latter was then added to ice/water; this mixture was then extracted several times with methylene chloride and methyl-t-butyl ether. Drying and concentrating left a residue of 1.74 g (98% of theory) of the substituted dithiane, which was subsequently hydrogenated in tetrahydrofuran, at 40° C. and over the course of 12 h, using Raney nickel and hydrogen. After the catalyst had been separated off, the residue was purified by chromatography (silica gel, methylene chloride/methanol). Yield: 700 mg (49% of theory). Colorless solid, m.p. 144-145° C.

C₂₉H₄₃N₇ (489).

EXAMPLE 23 3-{4-[4-(2-t-Butyl-6-trifluoromethylpyrimidin-4-yl)piperazin-1-yl]butyl}-4-methyl-5-phenyl-1,2,4-(4H)-triazole hydrochloride

The compound was prepared, by a method similar to Example 22, using the chlorine compound from Example 1, A.3.

C₂₉H₃₄F₃N₇ (502)

1H NMR (CDCl₃): 1.3 (s,9H); 1.7 (m,2H); 1.9 (q,2H); 2.4 (t,2H); 2.5 (t,4H); 2.8 (t,2H); 3.6 (s,3H); 3.75 (m,4H); 6.6 (s,1H); 7.4 (m,3H); 7.6 (m,2H).

EXAMPLE 24 3-{3-[4-(2-t-Butyl-6-trifluoromethylpyrimidin-4-yl)piperazin-1-yl]propylmercapto}-5-(2,5-dimethylfuran-3-yl)-4-methyltriazole hydrochloride

2,5-Dimethylfuran-3-yl-3-mercapto-4-methyl-1,2,4-(4H)-triazole was obtained by reacting 2,5-dimethylfuran-3-carbonyl chloride with N-methylthiosemicarbazide and subsequently cyclizing in accordance with the method of Kubota and Uda, Chem. Pharm. Bull. (1975), 23, 955-966.

C₉H₁₁N₃OS (209).

1H NMR (CDCl₃): 2.2 (s,3H); 2.3 (s,3H); 3.5 (s,3H); 6.5 (1H).

The abovementioned compound was obtained by reacting by a method similar to Example 1B. M.p. 190-192° C.

C₂₅H₃₄F₃N₇OS HCl (574)

EXAMPLE 25 3-{3-[4-2-t-Butyl-6-trifluoromethylpyrimidin-4-yl)piperazin-1-yl]propylmercapto}-5-(pyrazin-2-yl)-4-methyltriazole hydrochloride

3-Mercapto-4-methyl-5-pyrazin-2-yl-1,2,4-(4H)-triazole was obtained by reacting pyrazine-2-carbonyl chloride by a method similar to the method of Kubota and Uda in Example 24.

The abovementioned compound was likewise prepared by a method similar to Example 1B. M.p. 164-169° C.

C₂₃H₃₁F₃N₉ (522).

EXAMPLE 65 3-(3-(4-(2-t-Butyl-6-trifluoromethyl-pyrimidin-4-yl)piperazin-1-yl)propylmercapto-4-methyl-5-((1H)-tetrazolyl-5)-1.2.4(4H)-triazole

a) 3-(3-(4-(2-t-Butyl-6-trifluoromethylpyrimidine-4-yl)piperazin-1-yl)propylmercapto-4-methyl-1.2.4(4H)-triazole-5-carboxamide

950 mg (6.0 mmol) 5-mercapto-4-methyl-1.2.4(4H)-triazole-3-carboxamide were heated to 100° C. together with 2.2 g (6.0 mmol) of the chlorine base obtained according to example 1.A3 and 144 mg lithiumhydroxide (6.0 mmol) in 17 ml DMF for 3 h while stirring 100° C. The mixture was then cooled, 100 ml of water were added and the mixture was extracted with methyl-t-butyl ether. Then the solvent layer was dried and evaporated. The residue was purified by chromatography (silica gel, methylene chloride methanol 95:5).

Yield: 1.65 g (57% of th.)

mp: 141-143° C.

C₂₀H₂₉F₃N₈OS (MG 486)

b) 3-(3-(4-(2-t-Butyl-6-trifluoromethylpyrrimidine-4-yl)piperazin-1-yl)propylmercapto-5-cyano-4-methyl-1.2.4(4H)-triazole

1.15 g (24.0 mmol) of the above described compound were dissolved in 20 ml of methylene chloride and 2 ml (12.0 mmol) of dipropylethylamine, cooled to 0° C. and 0.5 ml trifluoroacetanhydride were slowly added thereto. After stirring for 3 h at room temperature the mixture was washed twice with water, then with a 20% strength solution of NaHSO₄, with a saturated solution of NaHCO₃ and a saline solution; then the organic layer was dried and evaporated. The residue was 0.9 g of an oil (81% of th.). A sample was transferred into the hydrochloride with etherial hydrogen chloride.

mp: 220-222° C.

C₂₀H₂₇F₃N₈S (MG 468)

C₂₀H₂₈ClF₃N₈S (MG 503,5)

c) 5-(3-(4-(2-t-Butyl-6-trifluoromethylpyrimidine-4-yl)piperazin-1-yl)propylmercapto-4-methyl-3-((1H)-tetrazolyl-5)-1.2.4(4H)-triazole.

0.8 g (1.7 mmol) of the above described substance were dissolved in 1 ml of DMF, then 122 mg (1.9 mmol) of sodiumazide and 100 mg (1.9 mmol) of ammonium chloride were added and the mixture was heated to 85° C. for 2 h while stirring. For the working-up a little water was added, the solution was adjusted to pH 7 with NaOH and extracted with methylene chloride. Drying and concentrating left a residue of ca. 1 g which was purified by chromatography (silica gel, methylene chloride/methanol 8:2).

Yield: 0.38 g (43% of th.)

Fp. 133° (decomposition)

C₂₀H₂₈F₃N₁₁S (MG 511)

The compounds listed in tables 2 to 9 were obtained in a similar way:

TABLE 2

Ar1 R1 T R7 Z R9 R10 X—Y A N—Me-2-Pyrrolyl Et N tBut N 4-MeOPh H CH₂—N COO—(CH₂)₄— 2-Me-4-Oxazolyl But N tBut N H OMe CH₂—N S—CH₂—CH═CH—CH₂— N—Me-2-Pyrrolyl But N iProp CH tBut H CH₂—CH S—(CH₂)₃— 4-Imidazolyl Me N tBut CH iProp H CH₂—N S—(CH₂)₇— 2,5-Di-methyl-furanyl-3- cBut N Pyrrolyl N Me H CH═C NH—(CH₂)₄ N—Me-2-Pyrrolyl Me N tBut N tBut H CH₂—CH S—(CH₂)₃— 2-Pyrrolyl Me N 2,4 OMe—Ph N Cl H CH₂—N O—(CH₂)₃— 2-Pyrazinyl- (CH₂)₄—OMe N tBut N 1-Pyrrolyl H CH₂—N —(CH₂)₈— 2-Methyl-pyridin-3-yl CH₂Ph CH iProp N H OMe CH₂—N —(CH₂)₄— 2-Pyrazinyl- cProp CH H N CH₃ OMe CH═C O—(CH₂)₃— 3-Br-Pyrimidin-5-yl Et N Prop N cHex H CH═C O—(CH₂)₄— Pyrimidin-3-yl Et N tBut N nHex H CH₂—N S—CH₂—C(CH₃)═CH—CH₂— N-Propyl-tetrazolyl CH₂Ph N iProp N H OMe CH₂—N S—(CH₂)₄— 2-Methyl-pyridin-3-yl cProp N H N CH₃ OMe CH═C O—(CH₂)₃— N-Ethyl-indol-3-yl Me N H N iProp OMe CH₂—N S—(CH₂)₃— Tetrazolyl- Et N tBut N H CH₃ CH₂—N —(CH₂)₄— 6-Chlor-biphenyl-2 Me CH tBut N tBut OMe CH₂—N CONH—(CH₂)₄— 4-Methylthiazol Me N 4-OMePh N Me Me CH₂—N S—(CH₂)₇— Tetrazonyl- iProp N tBut N Ph H CH₂—N CO—(CH₂)₃— N—Me-2-Pyrrolyl Prop N Me CH Pyrrolyl H CH═C CH₂—CH₂—C(CH₃)═CH—CH₂— 4-Imidazolyl cProp N nPropyl N tBut H CH═C NH—(CH₂)₃— 2-Pyrrolyl Me N 4-OMePh N Me Me CH═C S—(CH₂)₈— 3-Thienyl Me CH 4-OMePh N Me Me CH₂—N CH₂—CH₂—C(═CH₂)—CH₂— 2-Me-4-Oxazolyl Et N tBut N Pyrrolyl H CH₂—N S—CH₂—C(═CH₂)—CH₂— 2-Me-4-Oxazolyl cProp N tBut CH Me H CH₂—N S—CH₂—CH═CH—CH₂— N-Propyl-tetrazolyl Me N CF₃ CH Me Butyl CH═C CH₂—CH₂—CH(CH₃)—CH₂ 3-Thienyl cProp N CF₃ N Me Butyl CH═C CH₂—CH₂—CH(CH₃)—CH₂ N-Propyl-tetrazolyl Me N CF₃ N H H CH₂—N —(CH₂)₄— 3-Thienyl cBut N CHF₂ CH H H CH₂—N —(CH₂)₄— 2,5-Dimethyl-furanyl-3- Me N Pyrrolyl CH Me H CH═C NH—(CH₂)₄— Oxadiazol-2-yl Prop N Me N Pyrrolyl H CH₂—N —(CH₂)₄— N-Propyl-2-pyrrolyl Prop N Me N Pyrrolyl H CH═C CH₂—CH₂—C(CH₃)═CH—CH₂— 3-Benzthienyl iProp N tBut N Ph H CH₂—N CH₂—CH₂—CH(CH₃)—CH₂— 5-Methyl imidazol-4-yl Me N 2,4 OMe-Ph CH Cl H CH₂—N O—(CH₂)₃— 2-Aminothiazol-4yl Prop N Cl CH iProp H CH₂—N CH₂—CH₂—C(CH₃)═CH—CH₂— N—Me-2-Pyrrolyl iProp CH tBut N tBut H CH₂—CH S—(CH₂)₃— N-Propyl-2-pyrrolyl Prop N Me CH tBut H CH═C CH₂—CH₂—CH(CH₃)—CH₂— 3-Benzthienyl iProp N tBut CH H Ne CH₂—N S—CH₂—C(CH₃)═CH—CH₂— 2-Pyrrolyl Me CH iProp N Me H CH₂—CH NH—(CH₂)₃— 2-Phenyl-furan-3yl cProp N CF₃ CH CH CH CH═C S—(CH₂)₃ 3-Br-Pyrimidin-5-yl Me CH iProp N tBut H CH₂—N CO—(CH₂)₇— 2-Aminothiazol-4yl Et N CH Cl CH CH CH₂—N CONH—(CH₂)₄— 6 Me-Benzoindol-3-yl Me N iProp CH Furanyl H CH₂—N CH₂—CH₂—C(CH₃)═CH—CH₂— 2,5-Dimethyl-furanyl-3- cBut CH Pyrrolyl N Me H CH═C NH—(CH₂)₄— Tetrazolyl- iProp N tBut CH H Cl CH₂—N CO—(CH₂)₈— 4-Imidazolyl (CH₂)₄—OMe CH tBut N H H CH₂—N —(CH₂)₈— Pyrimidin-3-yl Et CH Pyrrolyl N cHex H CH═C S—(CH₂)₄— 4-Imidazolyl Me N iProp N iProp H CH₂—N S—(CH₂)₇— N-Propyl-tetrazolyl Et CH tBut N nHex H CH₂—N S—CH₂—C(CH₃)═CH—CH₂—

TABLE 3

R1 R2 R3 R4 R5 T R7 Z R9 R10 X—Y A Me H CN H CN N tBut N tBut H CH₂—CH S—(CH₂)₃— Me OMe H OMe H N iProp N iProp H CH₂—N S—(CH₂)₇— Me H H MeSO₂ H N H N CF₂Cl H CH₂—N O—(CH₂)₃— Me H Me CN H CH tBut N tBut H CH₂—N CONH—(CH₂)₄— cProp H Me CN H N nPropyl N tBut H CH═C NH—(CH₂)₃— Me OMe H tBut H N 4- N Me Me CH═C S—(CH₂)₈— OMePh Me H iProp H Me CH 4- N Me Me CH₂—N S—(CH₂)₇— OMePh Et H H H H N Me N Pyrrolyl H CH₂—N —(CH₂)₄— iProp H H H H N Pyrrolyl N Me H CH₂—N CO—(CH₂)₈— Et Me H Br Br CH tBut N Pyrrolyl H CH₂—N S—CH₂—C(═CH₂)—CH₂— Et H H 4-MePh H N tBut N 2-Napht H CH₂—N COO—(CH₂)₄— —(CH₂)₄—OMe H Cl Cl H N tBut N 1-Pyrrolyl H CH₂—N —(CH₂)₈— Prop Me H Br H CH Me N Pyrrolyl H CH₂—N S—CH₂—C(═CH₂)—CH₂— Et H MeSO₂ Me MeSO₂ N Prop N cHex H CH═C O—(CH₂)₄— Et Me H Br H N tBut N nHex H CH₂—N S—CH₂—C(CH₃)—CH—CH₂— But H OMe H OMe N tBut N H OMe CH₂—N S—CH₂—CH═CH—CH₂— CH₂Ph I OMe H H N iProp N H OMe CH₂—N S—(CH₂)₄— cProp H Me CN H N nPropyl CH tBut Me CH═C S—(CH₂)₇— cProp F H F H N H N CH₃ OMe CH═C O—(CH₂)₃— Me H iProp H H N 4- N Me Me CH₂—N S—(CH₂)₇— OMePh Me OMe H tBut H N 4- N Me Me CH₂—N CH₂—CH₂—C(═CH₂)—CH₂— OMePh iProp H CN CN H N tBut CH H Me CH═C S—CH₂—CH(CH₃)—CH₂— Et Me H Br H N tBut N Pyrrolyl H CH₂—N S—CH₂—C(═CH₂)—CH₂— Me H OMe H Prop N iProp N Furanyl H CH₂—N CH₂—CH₂—C(CH₃)═CH—CH₂— Me H CN H H N tBut CH tBut H CH₂—CH S—(CH₂)₃— Me OMe H OMe H N iProp CH iProp H CH₂—N —(CH₂)₄— Me H H MeSO₂ H N H C—Me CF₃ H CH₂—N CONH—(CH₂)₄ Me H iProp H H N Me CH Me H CH₂—N S—(CH₂)₇— Prop SO₂Me H SO₂Me H N 4- CH Pyrrolyl H CH═C CH₂—CH₂—C(CH₃)═CH—CH₂— OMePh Me OMe H tBut H N 4- CH Me Me CH₂—N CH₂—CH₂—C(═CH₂)—CH₂— OMePh Prop SO₂Me H SO₂Me H N Me N Pyrrolyl H CH═C CH₂—CH₂—C(CH₃)═CH—CH₂— iProp OMe Ph H H N tBut N Ph H CH₂—N CH₂—CH₂—CH(CH₃)—CH₂— H H Br H NH₂ N Cl CH tBut H CH₂—N S—CH₂—C(═CH₂)—CH₂— Prop H C≡CH H H CH tBut N H CH₃ CH₂—N CH₂—CH₂—CH(CH₃)—CH₂— cProp SO₂Me H SO₂Me H CH Me N Pyrrolyl H CH═C CH₂—CH₂—C(CH₃)═CH—CH₂— iProp OMe Ph H H CH tBut N 4-OMePh H CH₂—N —(CH₂)₄— Me H H H H N Me N H But CH═C —(CH₂)₈— Prop NO₂ H H Me N Me N Pyrrolyl H CH₂—N —(CH₂)₄— iProp H iProp H Me N tBut N Ph H CH₂—N CO—(CH₂)₃— Me OMe H tBut H CH 4- N Me Me CH₂—CH CH₂—CH₂—C(═CH₂)—CH₂— OMePh

TABLE 4

R1 R2 R3 R4 R5 R6 R7 R8 R9 R10 X—Y A Me OMe H tBut H H tBut H tBut H CH₂—N S—CH₂—C(═CH₂)—CH₂— cProp H H MeSO₂ H H tBut F Ph H CH₂—N O—(CH₂)₄— Me H iProp H H H tBut H 1-Pyrrolyl H CH₂—N S—CH₂—C(CH₃)═CH—CH₂— Prop SO₂Me H SO₂Me H H nPropyl H tBut H CH═C S—CH₂—CH═CH—CH₂— Me H Me CN H H CF₃ H tBut H CH₂—N S—(CH₂)₄— Me OMe H tBut H Me Me H iProp H CH₂—N S—CH₂—CH(CH₃)—CH₂ Me H H Cl Cl H iProp H p-OMe—Ph H CH₂—N O—(CH₂)₃— cProp H Me CN H OMe tBut CN CF₃ H CH═C S—(CH₂)₇— Et Me H Br Br H iProp H Me Me CH═C CH₂—CH₂—C(═CH₂)—CH₂— Et H H 4-MePh H H iProp H F OMe CH₂—N S—(CH₂)₇— —(CH₂)₄—OMe H Cl Cl H H CHF₂ H But H CH₂—N S—CH₂—C(═CH₂)—CH₂— Prop SO₂Me H SO₂Me H H Ph C≡CH tBut H CH₂—N CH₂—CH₂—C(CH₃)═CH—CH₂— iProp OMe Ph H H H CHF₂ H H H CH═C S—(CH₂)₃— cProp F H F H H CF₃ H H H CH₂—CH —(CH₂)₄—

TABLE 5

Ar1 R1 R6 R7 R8 R9 R10 X—Y A 4-Imidazolyl- Me H tBut H tBut H CH₂—N S—CH₂—C(═CH₂)—CH₂— 2-Pyrazinyl- cProp H tBut F Ph H CH₂—N O—(CH₂)₄— 2-Me-4-Oxazolyl- Me H tBut H i-Pyrrolyl H CH₂—N S—CH₂—C(CH₃)═CH—CH₂— 2-Pyrrolyl Prop H nPropyl H tBut H CH═C S—CH₂—CH═CH—CH₂— 3-Br-Pyrimidin-5-yl- Me H CF₃ H tBut H CH₂—N S—(CH₂)₄— Pyrimidin-3-yl- Me Me Me H iProp H CH₂—N S—CH₂—CH(CH₃)—CH₂ 6-Chlor-biphenyl-2- Me H iProp H p-OMe—Ph H CH₂—N O—(CH₂)₃— 2,5-Di-methyl-furanyl-3- cProp OMe tBut CN CF₃ H CH═C S—(CH₂)₇— N-Propyl-tetrazolyl- Et H iProp H Me Me CH═C CH₂—CH₂—C(═CH₂)—CH₂— N—Methyl-2-Pyrrolyl- Et H iProp H F OMe CH₂—N S—(CH₂)₇— 3-Thienyl —(CH₂)₄—OMe H CHF₂ H But H CH₂—N S—CH₂—C(═CH₂)—CH₂— 3-Benzthienyl- Prop H Ph C≡CH tBut H CH₂—N CH₂—CH₂—C(CH₃)═CH₂— 2-Me-4-Oxazolyl- iProp H CHF₂ H H H CH═C S—(CH₂)₃— 4-Methylthiazol- Et H CHF₂ H But H CH₂—N CH₂—CH₂—C(CH₃)═CH₂— 3-Benzthienyl- iProp H iProp H p-OMe—Ph H CH₂—N NH—(CH₂)₄— 5-Methyl imidazol-4-yl- Me But Me H H H CH₂—N O—(CH₂)₃— 2-Aminothiazol-4yl- Prop H H C≡CH But H CH₂—N —(CH₂)₄— N—Me-2-Pyrrolyl Me H CF₃ H tBut H CH═C CO—(CH₂)₃— 2-Me-4-Oxazolyl iProp H tBut F Ph H CH═C S—(CH₂)₉— 2,5-Dimethyl-furanyl- Me Me H CN H H CH₂—N S—CH₂—CH═CH—CH₂ N-Ethyl-indol-3-yl —(CH₂)₄—OMe H CHF₂ H H H CH═C S—(CH₂)₃— 2,5-Di-methyl-furanyl-3- iProp H iProp H 2,4-OMe-Ph Me CH₂—CH— —COO—(CH₂)₄— 2-Aminothiazol-4yl- Me H iProp H 2,4-OMe-Ph H CH═C— —S—CH₂═CH—CH—CH₂— 3-Br-Pyrimidin-5-yl- Me H Me H Et Me CH₂—N S—(CH₂)₃— 5-Ethyl imidazol-4-yl- cProp Prop H C═CH But H CH₂—N —(CH₂)₄— n-Butyl-tetrazolyl- But H Et CN OH H CH═C —(CH₂)₄— 3-Benzthienyl- Me H CHF₂ H H H CH₂—CH- S—(CH₂)₃— N—Me-2-Pyrrolyl Me H CF₃ H tBut H CH₂—CH- S—(CH₂)₃ Tetrazolyl- cProp H CF₃ H iProp H CH₂—CH- —(CH₂)₄— Oxadiazol-2-yl- cProp H CF₃ H H H CH═C —(CH₂)₄—

TABLE 6

Ar1 R1 R6 R8 R9 R10 X—Y A N—Me-2-Pyrrolyl Prop 4-MeOPh H tBut H CH₂—N —S—(CH₂)₇— 2-Me-4-Oxazolyl Me H H iProp Me CH₂—N S—CH₂—CH═CH—CH₂— 4-Imidazolyl Me iProp Me But H CH₂—N COO—(CH₂)₄ 2,5-Di-methyl-furanyl- But Me CC Me H CH═C (CH₂)₄— 3-Thienyl- Me H H Pyrrolyl Cl CH₂—CN S—CH₂—C(CH₃)═CH—CH₂— 2-Pyrazinyl- cProp H CN iProp OMe CH₂—N —(CH₂)₄— 3-Br-Pyrimidin-5-yl Hex H H iProp OMe CH₂—N O—(CH₂)₃— Pyrimidin-3-yl Et cHex H Prop H CH═C NH—(CH₂)₄ 2-Pyrazinyl- Et H H Pent Et CH₂—N —(CH₂)₄— 2-Methyl-pyridin-3-yl Me H Cl Me H CH₂—N CONH—(CH₂)₄— 2,5-Di-methyl-furanyl-3- cProp CH₃ H H OMe CH═C —(CH₂)₄— N-Ethyl-indol-3-yl- cProp CH₃ Me H OMe CH═C S—CH₂—C(═CH₂)CH₂ Tetrazolyl- Et cHex H Prop H CH═C S—(CH₂)₃— 3-Benzthienyl- iProp H H cProp But CH₂—N S—(CH₂)₈— N-Propyl-tetrazolyl CH₂Ph H H iProp OMe CH₂—N S—(CH₂)₄— 2-Aminothiazol-4yl- Me H CN CHF₂ H CH₂—N —(CH₂)₄—

TABLE 7

R1 R2 R3 R4 R5 R6 R8 R9 R10 X—Y A Prop H MeSO₂ Me MeSO₂ Et H tBut H CH₂—N COO—(CH₂)₄— Me Me H Br H H H tBut H CH₂—N S—CH₂—CH═CH—CH₂— Me H OMe H OMe iProp Me tBut H CH₂—N —(CH₂)₄— But OMe H OMe H Me C≡CH Pyrrolyl- H CH═C CONH—(CH₂)₄ Me H Me CN H H H Me Cl CH₂—N —(CH₂)₄— cProp F H F H H H iProp OMe CH₂—N S—CH₂—C(═CH₂)CH₂— cProp H iProp H Me CH₃ Me H OMe CH═C O—(CH₂)₃— Et OMe H tBut H cHex H Prop H CH═C S—(CH₂)₃— Et H H H CN nHex CN tBut H CH₂—N S—CH₂—C(CH₃)═CH—CH₂— Hex H H H H₂NSO₂ H H CHF₂ H CH₂—N —CO—(CH₂)₃— Me H H H H H H iProp H CH═C S—(CH₂)₃— CH₂Ph NO₂ H NO₂ H H H iProp OMe CH₂—N S—(CH₂)₄—

TABLE 8

Ar1 R1 T R7 Z R9 R10 X—Y—W A N—Me-2-Pyrrolyl- Et N tBut N 4-MeOPh H CH₂—N—CH₂ COO—(CH₂)₄— 2-Me-4-Oxazolyl- But N tBut N H OMe CH═C—CH₂ S—CH₂—CH═CH—CH₂— Oxadiazol-2-yl- Prop N Me N Pyrrolyl H CH₂—CH—CH₂ —(CH₂)₄— Tetrazolyl- iProp N tBut N Ph H CH₂—CH—CH₂ CO—(CH₂)₃— N—Me-2-Pyrrolyl Prop N Me CH Pyrrolyl H CH═C—CH₂ CH₂—CH₂—C(CH₃)═CH—CH₂— 4-Imidazolyl- cProp N nPropyl N tBut H CH₂—C═CH NH—(CH₂)₄— 2-Pyrrolyl Me N 4-OMePh N Me Me CH₂—N—CH₂ S—(CH₂)₈— N—Me-2-Pyrrolyl But N iProp CH tBut H CH₂—C═CH S—(CH₂)₃— N—Me-2-Pyrrolyl Me N tBut N tBut H CH₂—N—CH₂ S—(CH₂)₃— 2-Pyrrolyl Me N 2,4 OMe—Ph N Cl H CH₂—C═CH CONH—(CH₂)₄— 2-Pyrazinyl- (CH₂)₄—OMe N tBut N 1-Pyrrolyl H CH₂—C═CH O—(CH₂)₃— 2-Methyl-pyridin-3-yl- CH₂Ph CH iProp N H OMe CH₂—N—CH₂ —(CH₂)₄— 2-Pyrazinyl- cProp CH H N CH₃ OMe CH₂—N—CH₂ —(CH₂)₈— 3-Br-Pyrimidin-5-yl-- Et N Prop N cHex H CH═C—CH₂ O—(CH₂)₄— Pyrimidin-3-yl- Et N tBut N nHex H CH₂—C═CH S—CH₂—C(CH₃)═CH—CH₂— N-Propyl-tetrazolyl- CH₂Ph N iProp N H OMe CH₂—N—CH₂ S—(CH₂)₄— 2-Methyl-pyridin-3-yl- cProp N H N CH₃ OMe CH₂—N—CH₂ O—(CH₂)₃— 4-Imidazolyl-- Me N tBut CH iProp H CH₂—N—CH₂ S—(CH₂)₇— 2,5-Di-methyl-furanyl-3- cBut N Pyrrolyl N Me H CH₂—N—CH₂ NH—(CH₂)₄ N-Ethyl-indol-3-yl- Me N H N iProp OMe CH═C—CH₂ S—(CH₂)₃— Tetrazolyl- Et N tBut N H CH₃ CH₂—C═CH —(CH₂)₄— 6-Chlor-biphenyl-2 Me CH tBut N tBut OMe CH═C—CH₂ CONH—(CH₂)₄ 4-Methylthiazol- Me N 4-OMePh N Me Me CH═C—CH₂ S—(CH₂)₇— 3-Thienyl- cBut N CHF₂ CH H H CH₂—N—CH₂ —(CH₂)₄ 2,5-Di-methyl-furanyl-3- Me N Pyrrolyl CH Me H CH₂—N—CH₂ NH—(CH₂)₄ 3-Thienyl Me CH 4-OMePh N Me Me CH₂—N—CH₂ CH₂—CH₂—C(═CH₂)—CH₂— 2-Me-4-Oxazolyl Et N tBut N Pyrrolyl H CH₂—C═CH S—CH₂—C(═CH₂)—CH₂— 2-Me-4-Oxazolyl- cProp N tBut CH Me H CH₂—N—CH₂ CH₂—CH₂—CH(CH₃)—CH₂ N-Propyl-tetrazolyl- Me N CF₃ CH Me Butyl CH₂—N—CH₂ CH₂—CH₂—CH(CH₃)—CH₂ 3-Thienyl- cProp N CF₃ N Me Butyl CH₂—N—CH₂ S—CH₂—CH═CH—CH₂— N-Propyl-tetrazolyl- Me N CF₃ N H H CH₂—CH—CH₂ —(CH₂)₄ N-Propyl-2-Pyrrolyl- Prop N Me N Pyrrolyl H CH₂—N—CH₂ CH₂—CH₂—C(CH₃)═CH—CH₂— 3-Benzthienyl- iProp N tBut N Ph H CH₂—N—CH₂ CH₂—CH₂—CH(CH₃)—CH₂ 5-Methyl imidazol-4-yl- Me N 2,4 OMe-Ph CH Cl H CH═C—CH₂ O—(CH₂)₃— 2-Aminothiazol-4yl- Prop N Cl CH iProp H CH═C—CH₂ CH₂—CH₂—C(CH₃)═CH—CH₂— N—Me-2-Pyrrolyl iProp CH tBut N tBut H CH₂—CH—CH₂ S—(CH₂)₃— N-Propyl-2-Pyrrolyl Prop N Me CH tBut H CH═C—CH₂ CH₂—CH₂—CH(CH₃)—CH₂ 2-Pyrrolyl Me CH iProp N Me H CH₂—N—CH₂ N—(CH₂)₃— 2-Phenyl-furan-3yl- cProp N CF₃ CH CH CH CH₂—CH—CH₂ S—(CH₂)₃ 3-Br-Pyrimidin-5-yl- Me CH iProp N tBut H CH═C—CH₂ CO—(CH₂)₇— 2-Aminothiazol-4yl- Et N CH Cl CH CH CH₂—N—CH₂ CONH—(CH₂)₄— 6 Me-Benzoindol-3-yl Me N iProp CH Furanyl H CH₂—N—CH₂ CH₂—CH₂—C(CH₃)═CH—CH₂— 2,5-Di-methyl-furanyl-3- cBut CH Pyrrolyl N Me H CH₂—CH—CH₂ NH—(CH₂)₄ Tetrazolyl- iProp N tBut CH H Cl CH₂—N—CH₂ CO—(CH₂)₈ 4-Imidazolyl- (CH₂)₄—OMe CH tBut N H H CH₂—N—CH₂ —(CH₂)₈— Pyrimidin-3-yl- Et CH Pyrrolyl N cHex H CH═C—CH₂ S—(CH₂)₄— 4-Imidazolyl- Me N iProp N iProp H CH₂—CH—CH₂ S—(CH₂)₇— N-Propyl-tetrazolyl- Et CH tBut N nHex H CH₂—N—CH₂ S—CH₂—C(CH₃)═CH—CH₂—

TABLE 9

Ar1 R1 R6 R7 R8 R9 R10 X—Y—W A 2-Pyrrolyl Prop H nPropyl H tBut H CH₂—CH—CH₂ S—CH₂—CH═CH—CH₂— N-Ethyl-indol-3-yl —(CH₂)₄—OMe H CHF₂ H H H CH₂—C═CH S—(CH₂)₃— 2,5-Di-methyl-furanyl-3- iProp H iProp H 2,4- Me CH═C—CH₂ —COO—(CH₂)₄— OMe—Ph 3-Br-Pyrimidin-5-yl- Me Me Me H iProp H CH₂—C═CH S—CH₂—CH(CH₃)—CH₂ Pyrimidin-3-yl- Hexyl H CF₃ H tBut H CH═C—CH₂ S—(CH₂)₄— 6-Chlor-biphenyl-2- Me H iProp H p-OMe—Ph H CH₂—N—CH₂ O—(CH₂)₃— N-Propyl-tetrazolyl- Et H iProp H Me Me CH₂—N—CH₂ CH₂—CH₂—C(═CH₂)—CH₂— N—Methyl-2-Pyrrolyl- Et H iProp H F OMe CH₂—C═CH S—(CH₂)₇— 3-Thienyl —(CH₂)₄—OMe H CHF₂ H But H CH₂—C═CH S—CH₂—C(═CH₂)—CH₂— 2,5-Di-methyl-furanyl-3- cProp OMe tBut CN CF₃ H CH₂—C═CH CO—(CH₂)₃— 2-Aminothiazol-4yl- Me H iProp H 2,4- H CH═C—CH₂ —S—CH₂—CH═CH—CH₂— OMe—Ph 3-Benzthienyl- Pentyl H Ph C≡CH tBut H CH₂—N—CH₂ CH₂—CH₂—C(CH₃)═CH—CH₂— 4-Methylthiazol- Et H CHF₂ H But H CH═C—CH₂ CH₂—CH₂—C(CH₃)═CH—CH₂— 3-Benzthienyl- iProp H iProp H p-OMe—Ph H CH₂—C═CH —CONH—(CH₂)₄ 5-Methyl imidazol-4-yl- Me But Me H H H CH₂—N—CH₂ O—(CH₂)₃— 2-Aminothiazol-4yl- Prop H H C≡CH But H CH₂—N—CH₂ —(CH₂)₄— 2-Me-4-Oxazolyl- iProp H CHF₂ H H H CH₂—N—CH₂ S—(CH₂)₃— N—Me-2-Pyrrolyl Me H CF₃ H tBut H CH₂—C—CH₂ S—(CH₂)₇— 2-Me-4-Oxazolyl iProp H tBut F Ph H CH₂—N—CH₂ CONH(CH₂)₄— 2,5-Dimethyl-furanyl- Me Me H CN H H CH═C—CH₂ S—CH₂—CH═CH—CH₂ 3-Br-Pyrimidin-5-yl- Me H Me H Et Me CH₂—N—CH₂ S—(CH₂)₃— n-Butyl-tetrazolyl- But H Et CN OH H CH₂—N—CH₂ —(CH₂)₄— 3-Benzthienyl- Me H CHF₂ H H H CH₂—C═CH S—(CH₂)₃— N—Me-2-Pyrrolyl Me H CF₃ H tBut H CH₂—C—CH₂ S—(CH₂)₃ Tetrazolyl- cProp H iProp H CF₃ H CH₂—N—CH₂ —(CH₂)₄— Propyl-tetrazolyl- Et H CF₃ H nProp H CH₂—N—CH₂ —(CH₁₃)₄— Oxadiazol-2-yl- cProp H CF₃ H H H CH₂—N—CH₂ —(CH₂)₄— 5-Ethyl imidazol-4-yl- cProp Prop H C≡CH But H CH₂—N—CH₂ —(CH₂)₄— 4-Imidazolyl- Me H tBut H tBut H CH₂—N—CH₂ S—CH₂—C(═CH₂)—CH₂— 2-Pyrazinyl- cProp H tBut F Ph H CH═C—CH₂ O—(CH₂)₄— 2-Me-4-Oxazolyl- Me H tBut H 1-Pyrrolyl H CH₂—CH—CH₂ S—CH₂—C(CH₃)═CH—CH₂— 4-Pyrimidyl- Et H Pent H 2,4- H CH₂—N—CH₂ OMe—Ph Oxadiazol-2-yl- Hex H CF₃ H tBut H CH₂—N—CH₂ S—(CH₂)₄—

Examples of Pharmacological Administration Forms

Tablets of the following composition were molded, in a customary manner, on a compressed-tablet machine: A) Tablets 40 mg of the substance of Example 1 120 mg  of corn starch 13.5 mg   of gelatin 45 mg of lactose 2.25 mg   of Aerosil ® (chemically pure silicic acid which is finely divided to the submicroscopic level) 6.75 mg   of potato starch (as a 6% strength paste) B) Coated tablets 20 mg of the substance of Example 4 60 mg of core mass 70 mg of saccharifying mass

The core mass consists of 9 parts of corn starch, 3 parts of lactose and 1 part of vinylpyrrolidone/vinyl acetate 60:40 mixed polymer. The saccharifying mass consists of 5 parts of cane sugar, 2 parts of corn starch, 2 parts of calcium carbonate and 1 part of talc. The coated tablets which have been prepared in this way are then provided with a gastric juice-resistant coating.

Biological Investigations—Receptor-binding Studies

1) D₃-binding Test

Cloned human D₃ receptor-expressing CCL 1,3 mouse fibro-blasts, which can be obtained from Res. Biochemicals Internat., One Strathmore Rd., Natick, Mass. 01760-2418 USA, were used for the binding studies.

Cell Preparation

The D₃-expessing cells were multiplied in RPMI-1640 containing 10% fetal calf serum (GIBCO No. 041-32400 N); 100 U/ml penicillin and 0.2% streptomycin (GIBCO BRL, Gaithersburg, Md., USA). After 48 h, the cells were washed with PBS and incubated for 5 min with 0.05% trypsin-containing PBS. After that, the mixture was neutralized with medium and the cells were collected by centrifuging at 300 g. In order to lyse the cells, the pellet was briefly washed with lysis buffer (5mM tris-HCl, pH 7.4, containing 10% glycerol) and then incubated, at 4° C. for 30 min, at a concentration of 107 cells/ml of lysis buffer. The cells were centrifuged at 200 g for 10 min and the pellet was stored in liquid nitrogen.

Binding Tests

For the D₃ receptor-binding test, the membranes were suspended in incubation buffer (50 mM tris-HCl, pH 7.4, containing 120 mM NaCl, 5 mM KCl, 2 mM CaCl₂, 2 mM MgCl₂, 10 μM quinolinol, 0.1% of ascorbic acid and 0.1% BSA) at a concentration of approx. 10⁶ cells/250 μl of test mixture and incubated at 30° C. with 0.1 nM ¹²⁵iodosulpride in the presence and absence of test substance. The nonspecific binding was determined using 10⁻⁶M spiperone.

After 60 min, the free and the bound radio ligand were separated by filtration through GF/B glass fiber filters (Whatman, England) on a Skatron cell collector (Skatron, Lier, Norway) and the filters were washed with ice-cold tris-HCl buffer, pH 7.4. The radioactivity which had collected on the filters was quantified using a Packard 2200 CA liquid scintillation counter.

The K_(i) values were determined by means of nonlinear regression analysis using the LIGAND program.

2) D₂-binding Test

Cell Culture

HEK-293 cells, possessing stably expressed human dopamine D2A receptors, were cultured in RPMI 1640 containing Glutamax I™ and 25 mM HEPES containing 10% fetal calf serum albumin. All the media contained 100 units of pencillin per ml and 100 μg/ml streptomycin. The cells were kept at 37° C. in a moist atmosphere containing 5% Co₂.

The cells were prepared for the binding studies by being trypsinized (0.05% trypsin solution) at room temperature for 3-5 minutes. After that, the cells were centrifuged at 250 g for 10 minutes and treated, at 4° C. for 30 minutes, with lysis buffer (5 mM tris-HCl, 10% glycerol, pH 7.4). Following centrifugation at 250 g for 10 minutes, the residue was stored at −20° C. until used.

Receptor Binding Tests

Dopamine D₂ receptor “low affinity state” using ¹²⁵I-spiperone (81 TBq/mmol, Du Pont de Nemours, Dreieich)

The mixtures (1 ml) were composed of 1×10⁵ cells in incubation buffer (50 mM tris, 120 mM NaCl, 5 mM KCl, 2 mM MgCl₂ and 2 mM CaCl₂, pH 7.4 with HCl) and 0.1 nM ¹²⁵I-spiperone (total binding) or, in addition, 1 μM haloperidol (nonspecific binding) or test substance.

After having been incubated at 25° C. for 60 minutes, the mixtures were filtered through GF/B glass fiber filters (Whatman, England) on a Skatron cell collector (Zinsser, Frankfurt) and the filters were washed with ice-cold 50 mM tris-HCl buffer, pH 7.4. The radioactivity which had collected on the filters was quantified using a Packard 2200 CA liquid scintillation counter.

The evaluation was carried out as described under a).

The K_(i) values were determined by means of nonlinear regression analysis using the LIGAND program or by converting the IC₅₀ values with the aid of the formula of Cheng and Prusoff.

In these tests, the novel compounds exhibit very good affinities for the D₃ receptor (<1 μmolar, in particular <100 nmolar) and high selectivities in relation to the D₃ receptor. 

We claim:
 1. A triazole compound of formula I

where Ar¹ is phenyl, naphthyl or a 5- or 6-membered heterocyclic aromatic ring having from 1 to 4 heteroatoms which are independently selected from O, S and N, where Ar¹ is unsubstituted or substituted by 1, 2, 3 or 4 substituents selected from C₁-C₆-alkyl which is unsubstituted or substituted by OH, OC₁-C₆-alkyl, halogen or phenyl, C₁-C₆-alkoxy, C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₃-C₆-cycloalkyl, halogen, CN, COOR², NR²R², NO₂, SO₂R², SO₂NR²R², OH, and phenyl which is unsubstituted or substituted by C₁-C₆-alkyl, OC₁-C₆-alkyl, NR²R², CN, CF₃, CHF₂, or halogen, and where the 5- or 6-membered heterocyclic ring may be fused to a phenyl ring; A is a straight-chain or branched C₄-C₁₀-alkylene group or a straight-chain or branched group consisting of from 4 to 11 members selected from the group of from 3 to 10 methylene members and at least one member Z, wherein Z is selected from O, S, NR², CONR², COO, CO, a double bond and a triple bond, and the member(s) Z is(are) arranged within the chain linking the triazole ring to B between methylene members and/or between the triazole ring and a methylene member; B is a radical of the formula:

Ar² is phenyl, pyridyl, pyrimidinyl or triazinyl, where Ar² is unsubstituted or substituted by from 1 to 4 substituents selected from OR², C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₁-C₆-alkoxy-C₁-C₆-alkyl, halogen-C₁-C₆-alkyl, halogen-C₁-C₆-alkoxy, halogen, CN, NO₂, SO₂R², NR²R², SO₂NR²R², a 5- or 6-membered carbocyclic, aromatic or non-aromatic ring and a 5- or 6-membered, heterocyclic aromatic or non-aromatic ring having from 1 or 2 heteroatoms which are selected from O, S and N, where the carbocyclic or heterocyclic ring is unsubstituted or substituted by C₁-C₆-alkyl, phenyl, phenoxy, halogen, OC₁-C₆-alkyl, OH, NO₂ or CF₃ and/or is optionally fused to a phenyl ring; and where Ar² may be fused to a carbocyclic aromatic or non-aromatic ring or 5- or 6-membered heterocyclic aromatic or non-aromatic ring having 1 or 2 heteroatoms, selected from O, S and N, R¹ is C₃-C₆-cycloalkyl or C₁-C₆-alkyl which is unsubstituted or substituted by OH or OC₁-C₆-alkyl; the radicals R², which can be identical or different, are H or C₁-C₆-alkyl which is unsubstituted or substituted by OH, OC₁-C₆-alkyl or phenyl; or a salt thereof with a physiologically tolerated acid.
 2. The compound of formula I defined in claim 1, where A is a C₄-C₁₀-alkylene group or a group consisting of from 4 to 11 members selected from the group of from 3 to 10 methylene members and at least one group Z, wherein Z is selected from O, S, a double bond and triple bond.
 3. The compound of formula I defined in claim 1, where Ar¹ is phenyl, naphthyl, pyrrolyl, thienyl, furanyl, thiazolyl, imidazolyl, oxazolyl, oxadiazolyl, tetrazolyl, isoxazolyl, pyridinyl, pyrazinyl, pyrimidinyl, benzthiophenyl, indolyl or benzofuranyl, where Ar¹ is optionally substituted or fused as indicated in claim
 1. 4. The compound of formula I defined in claim 3, where Ar¹ is phenyl, thienyl, furanyl, tetrazolyl, pyrrolyl or pyrazinyl, where Ar¹ is optionally substituted as indicated in claim
 3. 5. The compound of formula I defined in claim 1, where Ar¹ is unsubstituted or substituted by 1, 2, 3 or 4 substituents selected from CN, C₁-C₆-alkyl, OH, OC₁-C₆-alkyl, phenyl and halogen.
 6. The compound of formula I defined in claim 1, where R¹ is C₁-C₆-alkyl or C₃-C₆-cycloalkyl.
 7. The compound of formula I defined in claim 1, where Ar² is phenyl, pyridinyl or pyrimidinyl and wherein Ar² is unsubstituted or carries one or two substituents selected from C₁-C₆-alkyl, C₂-C₆-alkynyl, halogen, CN, halogen-C₁-C₆-alkyl, OC₁-C₆-alkyl, NO₂, phenyl pyrrolyl, imidazolyl, pyrazolyl thienyl, indolyl, cyclopentyl and cyclohexyl.
 8. The compound of formula I defined in claim 7, wherein the substituent(s) is/are selected from C₁-C₆-alkyl, phenyl, NO₂, and halogen-C₁-C₆-alkyl.
 9. The compound of formula I defined in claim 7, wherein the substituent(s) is/are selected from CF₃, CHF₂ and CF₂Cl.
 10. A compound of formula I

where Ar¹ is phenyl which is unsubstituted or substituted by C₁-C₆-alkyl, OC₁-C₆-alkyl, CN, phenyl or halogen; A is a straight-chain or branched C₄-C₁₀-alkylene group or a straight-chain or branched group consisting of from 4 to 11 members selected from the group of from 3 to 10 methylene members and at least one member Z, wherein Z is selected from O, S, NR², CONR², COO, CO, a double bond and a triple bond, is

10 and Ar² is pyrimidinyl which is unsubstituted or substituted by C₁-C₆-alkyl, halogen-C₁-C₆-alkyl, halogen-C₁-C₆-alkoxy, pyrrolyl or indolyl; R¹ is C₃-C₆-cycloalkyl or C₁-C₆-alkyl which is unsubstituted or substituted by OH or OC₁-C₆-alkyl; the radicals R², which can be identical or different, are H or C₁-C₆-alkyl which is unsubstituted or substituted by OH, OC₁-C₆-alkyl or phenyl; or a salt thereof with a physiologically tolerated acid.
 11. The compound of formula I defined in claim 10, where Ar¹ is phenyl which is unsubstituted or substituted by C₁-C₆-alkyl, OC₁-C₆-alkyl or halogen, and A is —S(CH₂)₃₋₁₀— or —(CH₂)₄₋₁₀—.
 12. A pharmaceutical composition comprising an effective amount of at least one compound of formula I as defined in claim 1, and a physiologically acceptable carrier substance and/or auxiliary substance.
 13. A method for the treatment of a disease which responds to dopamine D3 receptor antagonists or dopamine D3 agonists and which is selected from the group of schizophrenia, depressions, neuroses, psychoses, Parkinson's disease and anxiety, which method comprises administering an effective amount of at least one compound of formula I

where Ar¹ is phenyl, naphthyl or a 5- or 6-membered heterocyclic aromatic ring having from 1 to 4 heteroatoms which are independently selected from O, S and N, where Ar¹ is unsubstituted or substituted by 1, 2, 3 or 4 substituents selected from C₁-C₆-alkyl which is unsubstituted or substituted by OH, OC₁-C₆-alkyl, halogen or phenyl, C₁-C₆-alkoxy, C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₃-C₆-cycloalkyl, halogen, CN, COOR², NR²R², NO₂, SO₂R², SO₂NR²R², OH, and phenyl which is unsubstituted or substituted by C₁-C₆-alkyl, OC₁-C₆-alkyl, NR²R², CN, CF₃, CHF₂, or halogen, and where the 5- or 6-membered heterocyclic ring may be fused to a phenyl ring; A is a straight-chain or branched C₄-C₁₀-alkylene group or a straight-chain or branched group consisting of from 4 to 11 members selected from the group of from 3 to 10 methylene members and at least one member Z, wherein Z is selected from O, S, NR², CONR², COO, CO, a double bond and a triple bond, B is a radical of the formula:

Ar² is phenyl, pyridyl, pyrimidinyl or triazinyl, where Ar² is unsubstituted or substituted by from 1 to 4 substituents selected from OR², C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₁-C₆-alkoxy-C₁-C₆-alkyl, halogen-C₁-C₆-alkyl, halogen-C_(l)-C₆-alkoxy, halogen, CN, NO₂, SO₂R², NR²R², SO₂NR²R², a 5- or 6-membered carbocyclic, aromatic or non-aromatic ring and a 5- or 6-membered, heterocyclic aromatic or non-aromatic ring having from 1 or 2 heteroatoms which are selected from O, S and N, where the carbocyclic or heterocyclic ring is unsubstituted or substituted by C₁-C₆-alkyl, phenyl, phenoxy, halogen, OC₁-C₆-alkyl, OH, NO₂ or CF₃ and/or is optionally fused to a phenyl ring; and where Ar² may be fused to a carbocyclic aromatic or non-aromatic ring or 5- or 6-membered heterocyclic aromatic or non-aromatic ring having 1 or 2 heteroatoms, selected from O, S and N, R¹ is C₃-C₆-cycloalkyl or C_(l)-C₆-alkyl which is unsubstituted or substituted by OH, OC₁-C₆-alkyl or phenyl; the radicals R², which can be identical or different, are H or C₁-C₆-alkyl which is unsubstituted or substituted by OH, OC₁-C₆-alkyl or phenyl; or a salt thereof with a physiologically tolerated acid, to a subject in need of such treatment.
 14. A compound of formula VIII

where Ar¹ is phenyl, naphthyl or a 5- or 6-membered heterocyclic aromatic ring having from 1 to 4 heteroatoms which are independently selected from O, S and N, where Ar¹ is unsubstituted or substituted by 1, 2, 3 or 4 substituents selected from C₁-C₆-alkyl which is unsubstituted or substituted by OH, OC₁-C₆-alkyl, halogen or phenyl, C₁-C₆-alkoxy, C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₃-C₆-cycloalkyl, halogen, CN, COOR², NR²R², NO₂, SO₂R², SO₂NR²R², OH, and phenyl which is unsubstituted or substituted by C₁-C₆-alkyl, OC₁-C₆-alkyl, NR²R², CN, CF₃, CHF₂, or halogen, and where the 5- or 6-membered heterocyclic ring may be fused to a phenyl ring; R¹ is C₃-C₆-cycloalkyl or C₁-C₆-alkyl which is unsubstituted or substituted by OH or OC₁-C₆-alkyl; the radicals R², which can be identical or different, are H or C₁-C₆-alkyl which is unsubstituted or substituted by OH, OC₁-C₆-alkyl or phenyl. 